Special Issue "DNA Damage Response"

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A special issue of Biomolecules (ISSN 2218-273X).

Deadline for manuscript submissions: closed (30 June 2015)

Special Issue Editors

Guest Editor
Prof. Dr. Wolf-Dietrich Heyer

Professor and Chair, Department of Microbiology & Molecular , University of California, Davis, One Shields Avenue, Davis, CA 95616, USA
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Fax: +1 530 752 3011
Interests: regulation and mechanisms of homologous recombination; genome stability; DNA damage response
Guest Editor
Prof. Dr. Thomas Helleday

Torsten and Ragnar Söderberg Professor of Translational Medicine Science for Life Laboratory, Division of Translational Medicine and Chemical Biology Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Box 1031, S-171 21 Stockholm, Sweden
Website | E-Mail
Interests: DNA damage signalling; homologous recombination at replication forks in mammalian cells
Guest Editor
Prof. Dr. Fumio Hanaoka

Department of Life Science, Faculty of Science, Gakushuin University, 1-5-1 Mejiro, Toshima-ku, Tokyo 171-8588, Japan
Website | E-Mail
Fax: +81 3 5992 1029
Interests: molecular mechanisms of translesion synthesis and nucleotide excision repair; understanding the cellular responses to DNA damages; interactions between cell cycle control and DNA repair

Special Issue Information

Dear Colleagues,

In two ground breaking publications in Science in 1988/1989, Ted Weinert and Lee Hartwell conceptualized many previous observations on how cells react to genotoxic stress by developing the checkpoint model. They validated the concept by isolating the first DNA damage checkpoint mutant in the budding yeast Saccharomyces cerevisiae and showing that RAD9 controlled transient cell cycle arrest after ionizing radiation exposure. These seminal discoveries propelled an entire field that is still thriving. We realize over 20 years later that the cell cycle response is only one, albeit critical aspect, of a much broader cellular answer to genotoxic stress that is now called the DNA Damage Response. This issue intends to showcase up to date reviews about emerging concepts from future leaders in this exciting area of research.

We thus invite submission review manuscripts (although original research manuscripts are welcome as well) that cover any aspect of the DNA damage response, a complex web of interconnected pathways that control many cellular processes including DNA replication, DNA repair, the mitotic and meiotic cell cycle, and nuclear architecture. The DNA damage response is intricately linked to cancer. Defects in the DNA damage response predispose humans to cancer, and many forms of anti-cancer treatment involve inducing localized or systemic DNA damage. Thus insights into the fundamental mechanisms of the DNA damage response are poised for translation into clinical practice.

We look forward to reading your contributions.

Prof. Dr. Wolf-Dietrich Heyer
Prof. Dr. Thomas Helleday
Prof. Dr. Fumio Hanaoka
Guest Editors

Submission

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Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 600 CHF (Swiss Francs). English correction and/or formatting fees of 250 CHF (Swiss Francs) will be charged in certain cases for those articles accepted for publication that require extensive additional formatting and/or English corrections.


Keywords

  • DNA damage
  • DNA checkpoints
  • DNA repair
  • DNA replication
  • genome instability
  • heterochromatin
  • cell cycle control

Published Papers (33 papers)

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Research

Jump to: Review, Other

Open AccessArticle Decorin Content and Near Infrared Spectroscopy Analysis of Dried Collagenous Biomaterial Samples
Biomolecules 2012, 2(4), 622-634; doi:10.3390/biom2040622
Received: 10 October 2012 / Revised: 30 November 2012 / Accepted: 3 December 2012 / Published: 14 December 2012
Cited by 1 | PDF Full-text (358 KB) | HTML Full-text | XML Full-text
Abstract
The efficient removal of proteoglycans, such as decorin, from the hide when processing it to leather by traditional means is generally acceptable and beneficial for leather quality, especially for softness and flexibility. A patented waterless or acetone dehydration method that can generate a
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The efficient removal of proteoglycans, such as decorin, from the hide when processing it to leather by traditional means is generally acceptable and beneficial for leather quality, especially for softness and flexibility. A patented waterless or acetone dehydration method that can generate a product similar to leather called Dried Collagenous Biomaterial (known as BCD) was developed but has no effect on decorin removal efficiency. The Alcian Blue colorimetric technique was used to assay the sulfated glycosaminoglycan (sGAG) portion of decorin. The corresponding residual decorin content was correlated to the mechanical properties of the BCD samples and was comparable to the control leather made traditionally. The waterless dehydration and instantaneous chrome tanning process is a good eco-friendly alternative to transforming hides to leather because no additional effects were observed after examination using NIR spectroscopy and additional chemometric analysis. Full article
(This article belongs to the Special Issue DNA Damage Response)
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Open AccessArticle Human DNA Glycosylase NEIL1’s Interactions with Downstream Repair Proteins Is Critical for Efficient Repair of Oxidized DNA Base Damage and Enhanced Cell Survival
Biomolecules 2012, 2(4), 564-578; doi:10.3390/biom2040564
Received: 15 October 2012 / Revised: 7 November 2012 / Accepted: 9 November 2012 / Published: 15 November 2012
Cited by 8 | PDF Full-text (833 KB) | HTML Full-text | XML Full-text
Abstract
NEIL1 is unique among the oxidatively damaged base repair-initiating DNA glycosylases in the human genome due to its S phase-specific activation and ability to excise substrate base lesions from single-stranded DNA. We recently characterized NEIL1’s specific binding to downstream canonical repair and non-canonical
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NEIL1 is unique among the oxidatively damaged base repair-initiating DNA glycosylases in the human genome due to its S phase-specific activation and ability to excise substrate base lesions from single-stranded DNA. We recently characterized NEIL1’s specific binding to downstream canonical repair and non-canonical accessory proteins, all of which involve NEIL1’s disordered C-terminal segment as the common interaction domain (CID). This domain is dispensable for NEIL1’s base excision and abasic (AP) lyase activities, but is required for its interactions with other repair proteins. Here, we show that truncated NEIL1 lacking the CID is markedly deficient in initiating in vitro repair of 5-hydroxyuracil (an oxidative deamination product of C) in a plasmid substrate compared to the wild-type NEIL1, thus suggesting a critical role of CID in the coordination of overall repair. Furthermore, while NEIL1 downregulation significantly sensitized human embryonic kidney (HEK) 293 cells to reactive oxygen species (ROS), ectopic wild-type NEIL1, but not the truncated mutant, restored resistance to ROS. These results demonstrate that cell survival and NEIL1-dependent repair of oxidative DNA base damage require interactions among repair proteins, which could be explored as a cancer therapeutic target in order to increase the efficiency of chemo/radiation treatment. Full article
(This article belongs to the Special Issue DNA Damage Response)
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Review

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Open AccessReview Cooperativity of the SUMO and Ubiquitin Pathways in Genome Stability
Biomolecules 2016, 6(1), 14; doi:10.3390/biom6010014
Received: 16 January 2016 / Revised: 17 February 2016 / Accepted: 23 February 2016 / Published: 25 February 2016
Cited by 4 | PDF Full-text (613 KB) | HTML Full-text | XML Full-text
Abstract
Covalent attachment of ubiquitin (Ub) or SUMO to DNA repair proteins plays critical roles in maintaining genome stability. These structurally related polypeptides can be viewed as distinct road signs, with each being read by specific protein interaction motifs. Therefore, via their interactions with
[...] Read more.
Covalent attachment of ubiquitin (Ub) or SUMO to DNA repair proteins plays critical roles in maintaining genome stability. These structurally related polypeptides can be viewed as distinct road signs, with each being read by specific protein interaction motifs. Therefore, via their interactions with selective readers in the proteome, ubiquitin and SUMO can elicit distinct cellular responses, such as directing DNA lesions into different repair pathways. On the other hand, through the action of the SUMO-targeted ubiquitin ligase (STUbL) family proteins, ubiquitin and SUMO can cooperate in the form of a hybrid signal. These mixed SUMO-ubiquitin chains recruit “effector” proteins such as the AAA+ ATPase Cdc48/p97-Ufd1-Npl4 complex that contain both ubiquitin and SUMO interaction motifs. This review will summarize recent key findings on collaborative and distinct roles that ubiquitin and SUMO play in orchestrating DNA damage responses. Full article
(This article belongs to the Special Issue DNA Damage Response)
Open AccessReview Activation of the DNA Damage Response by RNA Viruses
Biomolecules 2016, 6(1), 2; doi:10.3390/biom6010002
Received: 28 September 2015 / Revised: 17 November 2015 / Accepted: 24 November 2015 / Published: 6 January 2016
Cited by 4 | PDF Full-text (843 KB) | HTML Full-text | XML Full-text
Abstract
RNA viruses are a genetically diverse group of pathogens that are responsible for some of the most prevalent and lethal human diseases. Numerous viruses introduce DNA damage and genetic instability in host cells during their lifecycles and some species also manipulate components of
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RNA viruses are a genetically diverse group of pathogens that are responsible for some of the most prevalent and lethal human diseases. Numerous viruses introduce DNA damage and genetic instability in host cells during their lifecycles and some species also manipulate components of the DNA damage response (DDR), a complex and sophisticated series of cellular pathways that have evolved to detect and repair DNA lesions. Activation and manipulation of the DDR by DNA viruses has been extensively studied. It is apparent, however, that many RNA viruses can also induce significant DNA damage, even in cases where viral replication takes place exclusively in the cytoplasm. DNA damage can contribute to the pathogenesis of RNA viruses through the triggering of apoptosis, stimulation of inflammatory immune responses and the introduction of deleterious mutations that can increase the risk of tumorigenesis. In addition, activation of DDR pathways can contribute positively to replication of viral RNA genomes. Elucidation of the interactions between RNA viruses and the DDR has provided important insights into modulation of host cell functions by these pathogens. This review summarises the current literature regarding activation and manipulation of the DDR by several medically important RNA viruses. Full article
(This article belongs to the Special Issue DNA Damage Response)
Open AccessReview A Novel Aspect of Tumorigenesis—BMI1 Functions in Regulating DNA Damage Response
Biomolecules 2015, 5(4), 3396-3415; doi:10.3390/biom5043396
Received: 7 August 2015 / Revised: 23 October 2015 / Accepted: 26 November 2015 / Published: 1 December 2015
Cited by 1 | PDF Full-text (905 KB) | HTML Full-text | XML Full-text
Abstract
BMI1 plays critical roles in maintaining the self-renewal of hematopoietic, neural, intestinal stem cells, and cancer stem cells (CSCs) for a variety of cancer types. BMI1 promotes cell proliferative life span and epithelial to mesenchymal transition (EMT). Upregulation of BMI1 occurs in multiple
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BMI1 plays critical roles in maintaining the self-renewal of hematopoietic, neural, intestinal stem cells, and cancer stem cells (CSCs) for a variety of cancer types. BMI1 promotes cell proliferative life span and epithelial to mesenchymal transition (EMT). Upregulation of BMI1 occurs in multiple cancer types and is associated with poor prognosis. Mechanistically, BMI1 is a subunit of the Polycomb repressive complex 1 (PRC1), and binds the catalytic RING2/RING1b subunit to form a functional E3 ubiquitin ligase. Through mono-ubiquitination of histone H2A at lysine 119 (H2A-K119Ub), BMI1 represses multiple gene loci; among these, the INK4A/ARF locus has been most thoroughly investigated. The locus encodes the p16INK4A and p14/p19ARF tumor suppressors that function in the pRb and p53 pathways, respectively. Its repression contributes to BMI1-derived tumorigenesis. BMI1 also possesses other oncogenic functions, specifically its regulative role in DNA damage response (DDR). In this process, BMI1 ubiquitinates histone H2A and γH2AX, thereby facilitating the repair of double-stranded DNA breaks (DSBs) through stimulating homologous recombination and non-homologous end joining. Additionally, BMI1 compromises DSB-induced checkpoint activation independent of its-associated E3 ubiquitin ligase activity. We review the emerging role of BMI1 in DDR regulation and discuss its impact on BMI1-derived tumorigenesis. Full article
(This article belongs to the Special Issue DNA Damage Response)
Open AccessReview DNA Damage Signalling and Repair Inhibitors: The Long-Sought-After Achilles’ Heel of Cancer
Biomolecules 2015, 5(4), 3204-3259; doi:10.3390/biom5043204
Received: 7 September 2015 / Accepted: 9 November 2015 / Published: 20 November 2015
Cited by 7 | PDF Full-text (2322 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
For decades, radiotherapy and chemotherapy were the two only approaches exploiting DNA repair processes to fight against cancer. Nowadays, cancer therapeutics can be a major challenge when it comes to seeking personalized targeted medicine that is both effective and selective to the malignancy.
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For decades, radiotherapy and chemotherapy were the two only approaches exploiting DNA repair processes to fight against cancer. Nowadays, cancer therapeutics can be a major challenge when it comes to seeking personalized targeted medicine that is both effective and selective to the malignancy. Over the last decade, the discovery of new targeted therapies against DNA damage signalling and repair has offered the possibility of therapeutic improvements in oncology. In this review, we summarize the current knowledge of DNA damage signalling and repair inhibitors, their molecular and cellular effects, and future therapeutic use. Full article
(This article belongs to the Special Issue DNA Damage Response)
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Open AccessReview The RNA Splicing Response to DNA Damage
Biomolecules 2015, 5(4), 2935-2977; doi:10.3390/biom5042935
Received: 12 August 2015 / Revised: 20 September 2015 / Accepted: 16 October 2015 / Published: 29 October 2015
Cited by 7 | PDF Full-text (2730 KB) | HTML Full-text | XML Full-text
Abstract
The number of factors known to participate in the DNA damage response (DDR) has expanded considerably in recent years to include splicing and alternative splicing factors. While the binding of splicing proteins and ribonucleoprotein complexes to nascent transcripts prevents genomic instability by deterring
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The number of factors known to participate in the DNA damage response (DDR) has expanded considerably in recent years to include splicing and alternative splicing factors. While the binding of splicing proteins and ribonucleoprotein complexes to nascent transcripts prevents genomic instability by deterring the formation of RNA/DNA duplexes, splicing factors are also recruited to, or removed from, sites of DNA damage. The first steps of the DDR promote the post-translational modification of splicing factors to affect their localization and activity, while more downstream DDR events alter their expression. Although descriptions of molecular mechanisms remain limited, an emerging trend is that DNA damage disrupts the coupling of constitutive and alternative splicing with the transcription of genes involved in DNA repair, cell-cycle control and apoptosis. A better understanding of how changes in splice site selection are integrated into the DDR may provide new avenues to combat cancer and delay aging. Full article
(This article belongs to the Special Issue DNA Damage Response)
Open AccessReview Novel Implications of DNA Damage Response in Drug Resistance of Malignant Cancers Obtained from the Functional Interaction between p53 Family and RUNX2
Biomolecules 2015, 5(4), 2854-2876; doi:10.3390/biom5042854
Received: 2 June 2015 / Revised: 17 September 2015 / Accepted: 16 October 2015 / Published: 23 October 2015
Cited by 2 | PDF Full-text (609 KB) | HTML Full-text | XML Full-text
Abstract
During the lifespan of cells, their genomic DNA is continuously exposed to theendogenous and exogenous DNA insults. Thus, the appropriate cellular response to DNAdamage plays a pivotal role in maintaining genomic integrity and also acts as a molecularbarrier towards DNA legion-mediated carcinogenesis. The
[...] Read more.
During the lifespan of cells, their genomic DNA is continuously exposed to theendogenous and exogenous DNA insults. Thus, the appropriate cellular response to DNAdamage plays a pivotal role in maintaining genomic integrity and also acts as a molecularbarrier towards DNA legion-mediated carcinogenesis. The tumor suppressor p53 participatesin an integral part of proper regulation of DNA damage response (DDR). p53 is frequentlymutated in a variety of human cancers. Since mutant p53 displays a dominant-negative behavioragainst wild-type p53, cancers expressing mutant p53 sometimes acquire drug-resistantphenotype, suggesting that mutant p53 prohibits the p53-dependent cell death pathwayfollowing DNA damage, and thereby contributing to the acquisition and/or maintenance ofdrug resistance of malignant cancers. Intriguingly, we have recently found that silencing ofpro-oncogenic RUNX2 enhances drug sensitivity of aggressive cancer cells regardless of p53status. Meanwhile, cancer stem cells (CSCs) have stem cell properties such as drug resistance.Therefore, the precise understanding of the biology of CSCs is quite important to overcometheir drug resistance. In this review, we focus on molecular mechanisms behind DDR as wellas the serious drug resistance of malignant cancers and discuss some attractive approachesto improving the outcomes of patients bearing drug-resistant cancers. Full article
(This article belongs to the Special Issue DNA Damage Response)
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Open AccessReview ATM-Dependent Phosphorylation of All Three Members of the MRN Complex: From Sensor to Adaptor
Biomolecules 2015, 5(4), 2877-2902; doi:10.3390/biom5042877
Received: 27 August 2015 / Revised: 14 October 2015 / Accepted: 16 October 2015 / Published: 23 October 2015
Cited by 4 | PDF Full-text (2361 KB) | HTML Full-text | XML Full-text
Abstract
The recognition, signalling and repair of DNA double strand breaks (DSB) involves the participation of a multitude of proteins and post-translational events that ensure maintenance of genome integrity. Amongst the proteins involved are several which when mutated give rise to genetic disorders characterised
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The recognition, signalling and repair of DNA double strand breaks (DSB) involves the participation of a multitude of proteins and post-translational events that ensure maintenance of genome integrity. Amongst the proteins involved are several which when mutated give rise to genetic disorders characterised by chromosomal abnormalities, cancer predisposition, neurodegeneration and other pathologies. ATM (mutated in ataxia-telangiectasia (A-T) and members of the Mre11/Rad50/Nbs1 (MRN complex) play key roles in this process. The MRN complex rapidly recognises and locates to DNA DSB where it acts to recruit and assist in ATM activation. ATM, in the company of several other DNA damage response proteins, in turn phosphorylates all three members of the MRN complex to initiate downstream signalling. While ATM has hundreds of substrates, members of the MRN complex play a pivotal role in mediating the downstream signalling events that give rise to cell cycle control, DNA repair and ultimately cell survival or apoptosis. Here we focus on the interplay between ATM and the MRN complex in initiating signaling of breaks and more specifically on the adaptor role of the MRN complex in mediating ATM signalling to downstream substrates to control different cellular processes. Full article
(This article belongs to the Special Issue DNA Damage Response)
Open AccessReview Hsp90: A New Player in DNA Repair?
Biomolecules 2015, 5(4), 2589-2618; doi:10.3390/biom5042589
Received: 14 July 2015 / Revised: 8 September 2015 / Accepted: 10 September 2015 / Published: 16 October 2015
Cited by 3 | PDF Full-text (980 KB) | HTML Full-text | XML Full-text | Correction
Abstract
Heat shock protein 90 (Hsp90) is an evolutionary conserved molecular chaperone that, together with Hsp70 and co-chaperones makes up the Hsp90 chaperone machinery, stabilizing and activating more than 200 proteins, involved in protein homeostasis (i.e., proteostasis), transcriptional regulation, chromatin remodeling, and
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Heat shock protein 90 (Hsp90) is an evolutionary conserved molecular chaperone that, together with Hsp70 and co-chaperones makes up the Hsp90 chaperone machinery, stabilizing and activating more than 200 proteins, involved in protein homeostasis (i.e., proteostasis), transcriptional regulation, chromatin remodeling, and DNA repair. Cells respond to DNA damage by activating complex DNA damage response (DDR) pathways that include: (i) cell cycle arrest; (ii) transcriptional and post-translational activation of a subset of genes, including those associated with DNA repair; and (iii) triggering of programmed cell death. The efficacy of the DDR pathways is influenced by the nuclear levels of DNA repair proteins, which are regulated by balancing between protein synthesis and degradation as well as by nuclear import and export. The inability to respond properly to either DNA damage or to DNA repair leads to genetic instability, which in turn may enhance the rate of cancer development. Multiple components of the DNA double strand breaks repair machinery, including BRCA1, BRCA2, CHK1, DNA-PKcs, FANCA, and the MRE11/RAD50/NBN complex, have been described to be client proteins of Hsp90, which acts as a regulator of the diverse DDR pathways. Inhibition of Hsp90 actions leads to the altered localization and stabilization of DDR proteins after DNA damage and may represent a cell-specific and tumor-selective radiosensibilizer. Here, the role of Hsp90-dependent molecular mechanisms involved in cancer onset and in the maintenance of the genome integrity is discussed and highlighted. Full article
(This article belongs to the Special Issue DNA Damage Response)
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Open AccessReview The Role of the COP9 Signalosome and Neddylation in DNA Damage Signaling and Repair
Biomolecules 2015, 5(4), 2388-2416; doi:10.3390/biom5042388
Received: 30 June 2015 / Revised: 18 September 2015 / Accepted: 21 September 2015 / Published: 30 September 2015
Cited by 2 | PDF Full-text (1550 KB) | HTML Full-text | XML Full-text
Abstract
The maintenance of genomic integrity is an important process in organisms as failure to sense and repair damaged DNA can result in a variety of diseases. Eukaryotic cells have developed complex DNA repair response (DDR) mechanisms to accurately sense and repair damaged DNA.
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The maintenance of genomic integrity is an important process in organisms as failure to sense and repair damaged DNA can result in a variety of diseases. Eukaryotic cells have developed complex DNA repair response (DDR) mechanisms to accurately sense and repair damaged DNA. Post-translational modifications by ubiquitin and ubiquitin-like proteins, such as SUMO and NEDD8, have roles in coordinating the progression of DDR. Proteins in the neddylation pathway have also been linked to regulating DDR. Of interest is the COP9 signalosome (CSN), a multi-subunit metalloprotease present in eukaryotes that removes NEDD8 from cullins and regulates the activity of cullin-RING ubiquitin ligases (CRLs). This in turn regulates the stability and turnover of a host of CRL-targeted proteins, some of which have established roles in DDR. This review will summarize the current knowledge on the role of the CSN and neddylation in DNA repair. Full article
(This article belongs to the Special Issue DNA Damage Response)
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Open AccessReview Rho GTPases: Novel Players in the Regulation of the DNA Damage Response?
Biomolecules 2015, 5(4), 2417-2434; doi:10.3390/biom5042417
Received: 20 August 2015 / Revised: 2 September 2015 / Accepted: 9 September 2015 / Published: 30 September 2015
Cited by 1 | PDF Full-text (971 KB) | HTML Full-text | XML Full-text
Abstract
The Ras-related C3 botulinum toxin substrate 1 (Rac1) belongs to the family of Ras-homologous small GTPases. It is well characterized as a membrane-bound signal transducing molecule that is involved in the regulation of cell motility and adhesion as well as cell cycle progression,
[...] Read more.
The Ras-related C3 botulinum toxin substrate 1 (Rac1) belongs to the family of Ras-homologous small GTPases. It is well characterized as a membrane-bound signal transducing molecule that is involved in the regulation of cell motility and adhesion as well as cell cycle progression, mitosis, cell death and gene expression. Rac1 also adjusts cellular responses to genotoxic stress by regulating the activity of stress kinases, including c-Jun-N-terminal kinase/stress-activated protein kinase (JNK/SAPK) and p38 kinases as well as related transcription factors. Apart from being found on the inner side of the outer cell membrane and in the cytosol, Rac1 has also been detected inside the nucleus. Different lines of evidence indicate that genotoxin-induced DNA damage is able to activate nuclear Rac1. The exact mechanisms involved and the biological consequences, however, are unclear. The data available so far indicate that Rac1 might integrate DNA damage independent and DNA damage dependent cellular stress responses following genotoxin treatment, thereby coordinating mechanisms of the DNA damage response (DDR) that are related to DNA repair, survival and cell death. Full article
(This article belongs to the Special Issue DNA Damage Response)
Open AccessReview Molecular Process Producing Oncogene Fusion in Lung Cancer Cells by Illegitimate Repair of DNA Double-Strand Breaks
Biomolecules 2015, 5(4), 2464-2476; doi:10.3390/biom5042464
Received: 30 June 2015 / Revised: 10 September 2015 / Accepted: 14 September 2015 / Published: 30 September 2015
Cited by 3 | PDF Full-text (1822 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Constitutive activation of oncogenes by fusion to partner genes, caused by chromosome translocation and inversion, is a critical genetic event driving lung carcinogenesis. Fusions of the tyrosine kinase genes ALK (anaplastic lymphoma kinase), ROS1 (c-ros oncogene 1), or RET (rearranged during transfection) occur
[...] Read more.
Constitutive activation of oncogenes by fusion to partner genes, caused by chromosome translocation and inversion, is a critical genetic event driving lung carcinogenesis. Fusions of the tyrosine kinase genes ALK (anaplastic lymphoma kinase), ROS1 (c-ros oncogene 1), or RET (rearranged during transfection) occur in 1%–5% of lung adenocarcinomas (LADCs) and their products constitute therapeutic targets for kinase inhibitory drugs. Interestingly, ALK, RET, and ROS1 fusions occur preferentially in LADCs of never- and light-smokers, suggesting that the molecular mechanisms that cause these rearrangements are smoking-independent. In this study, using previously reported next generation LADC genome sequencing data of the breakpoint junction structures of chromosome rearrangements that cause oncogenic fusions in human cancer cells, we employed the structures of breakpoint junctions of ALK, RET, and ROS1 fusions in 41 LADC cases as “traces” to deduce the molecular processes of chromosome rearrangements caused by DNA double-strand breaks (DSBs) and illegitimate joining. We found that gene fusion was produced by illegitimate repair of DSBs at unspecified sites in genomic regions of a few kb through DNA synthesis-dependent or -independent end-joining pathways, according to DSB type. This information will assist in the understanding of how oncogene fusions are generated and which etiological factors trigger them. Full article
(This article belongs to the Special Issue DNA Damage Response)
Open AccessReview Arsenic Disruption of DNA Damage Responses—Potential Role in Carcinogenesis and Chemotherapy
Biomolecules 2015, 5(4), 2184-2193; doi:10.3390/biom5042184
Received: 14 August 2015 / Revised: 6 September 2015 / Accepted: 9 September 2015 / Published: 24 September 2015
Cited by 3 | PDF Full-text (426 KB) | HTML Full-text | XML Full-text
Abstract
Arsenic is a Class I human carcinogen and is widespread in the environment. Chronic arsenic exposure causes cancer in skin, lung and bladder, as well as in other organs. Paradoxically, arsenic also is a potent chemotherapeutic against acute promyelocytic leukemia and can potentiate
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Arsenic is a Class I human carcinogen and is widespread in the environment. Chronic arsenic exposure causes cancer in skin, lung and bladder, as well as in other organs. Paradoxically, arsenic also is a potent chemotherapeutic against acute promyelocytic leukemia and can potentiate the cytotoxic effects of DNA damaging chemotherapeutics, such as cisplatin, in vitro. Arsenic has long been implicated in DNA repair inhibition, cell cycle disruption, and ubiquitination dysregulation, all negatively impacting the DNA damage response and potentially contributing to both the carcinogenic and chemotherapeutic potential of arsenic. Recent studies have provided mechanistic insights into how arsenic interferes with these processes including disruption of zinc fingers and suppression of gene expression. This review discusses these effects of arsenic with a view toward understanding the impact on the DNA damage response. Full article
(This article belongs to the Special Issue DNA Damage Response)
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Open AccessReview Diversity of Endonuclease V: From DNA Repair to RNA Editing
Biomolecules 2015, 5(4), 2194-2206; doi:10.3390/biom5042194
Received: 29 June 2015 / Revised: 9 September 2015 / Accepted: 11 September 2015 / Published: 24 September 2015
Cited by 2 | PDF Full-text (907 KB) | HTML Full-text | XML Full-text
Abstract
Deamination of adenine occurs in DNA, RNA, and their precursors via a hydrolytic reaction and a nitrosative reaction. The generated deaminated products are potentially mutagenic because of their structural similarity to natural bases, which in turn leads to erroneous nucleotide pairing and subsequent
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Deamination of adenine occurs in DNA, RNA, and their precursors via a hydrolytic reaction and a nitrosative reaction. The generated deaminated products are potentially mutagenic because of their structural similarity to natural bases, which in turn leads to erroneous nucleotide pairing and subsequent disruption of cellular metabolism. Incorporation of deaminated precursors into the nucleic acid strand occurs during nucleotide synthesis by DNA and RNA polymerases or base modification by DNA- and/or RNA-editing enzymes during cellular functions. In such cases, removal of deaminated products from DNA and RNA by a nuclease might be required depending on the cellular function. One such enzyme, endonuclease V, recognizes deoxyinosine and cleaves 3' end of the damaged base in double-stranded DNA through an alternative excision repair mechanism in Escherichia coli, whereas in Homo sapiens, it recognizes and cleaves inosine in single-stranded RNA. However, to explore the role of endonuclease V in vivo, a detailed analysis of cell biology is required. Based on recent reports and developments on endonuclease V, we discuss the potential functions of endonuclease V in DNA repair and RNA metabolism. Full article
(This article belongs to the Special Issue DNA Damage Response)
Open AccessReview Managing Single-Stranded DNA during Replication Stress in Fission Yeast
Biomolecules 2015, 5(3), 2123-2139; doi:10.3390/biom5032123
Received: 31 July 2015 / Revised: 28 August 2015 / Accepted: 1 September 2015 / Published: 18 September 2015
PDF Full-text (4438 KB) | HTML Full-text | XML Full-text
Abstract
Replication fork stalling generates a variety of responses, most of which cause an increase in single-stranded DNA. ssDNA is a primary signal of replication distress that activates cellular checkpoints. It is also a potential source of genome instability and a substrate for mutation
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Replication fork stalling generates a variety of responses, most of which cause an increase in single-stranded DNA. ssDNA is a primary signal of replication distress that activates cellular checkpoints. It is also a potential source of genome instability and a substrate for mutation and recombination. Therefore, managing ssDNA levels is crucial to chromosome integrity. Limited ssDNA accumulation occurs in wild-type cells under stress. In contrast, cells lacking the replication checkpoint cannot arrest forks properly and accumulate large amounts of ssDNA. This likely occurs when the replication fork polymerase and helicase units are uncoupled. Some cells with mutations in the replication helicase (mcm-ts) mimic checkpoint-deficient cells, and accumulate extensive areas of ssDNA to trigger the G2-checkpoint. Another category of helicase mutant (mcm4-degron) causes fork stalling in early S-phase due to immediate loss of helicase function. Intriguingly, cells realize that ssDNA is present, but fail to detect that they accumulate ssDNA, and continue to divide. Thus, the cellular response to replication stalling depends on checkpoint activity and the time that replication stress occurs in S-phase. In this review we describe the signs, signals, and symptoms of replication arrest from an ssDNA perspective. We explore the possible mechanisms for these effects. We also advise the need for caution when detecting and interpreting data related to the accumulation of ssDNA. Full article
(This article belongs to the Special Issue DNA Damage Response)
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Open AccessReview Functional Role of NBS1 in Radiation Damage Response and Translesion DNA Synthesis
Biomolecules 2015, 5(3), 1990-2002; doi:10.3390/biom5031990
Received: 30 June 2015 / Revised: 11 August 2015 / Accepted: 13 August 2015 / Published: 20 August 2015
Cited by 3 | PDF Full-text (630 KB) | HTML Full-text | XML Full-text
Abstract
Nijmegen breakage syndrome (NBS) is a recessive genetic disorder characterized by increased sensitivity to ionizing radiation (IR) and a high frequency of malignancies. NBS1, a product of the mutated gene in NBS, contains several protein interaction domains in the N-terminus and C-terminus. The
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Nijmegen breakage syndrome (NBS) is a recessive genetic disorder characterized by increased sensitivity to ionizing radiation (IR) and a high frequency of malignancies. NBS1, a product of the mutated gene in NBS, contains several protein interaction domains in the N-terminus and C-terminus. The C-terminus of NBS1 is essential for interactions with MRE11, a homologous recombination repair nuclease, and ATM, a key player in signal transduction after the generation of DNA double-strand breaks (DSBs), which is induced by IR. Moreover, NBS1 regulates chromatin remodeling during DSB repair by histone H2B ubiquitination through binding to RNF20 at the C-terminus. Thus, NBS1 is considered as the first protein to be recruited to DSB sites, wherein it acts as a sensor or mediator of DSB damage responses. In addition to DSB response, we showed that NBS1 initiates Polη-dependent translesion DNA synthesis by recruiting RAD18 through its binding at the NBS1 C-terminus after UV exposure, and it also functions after the generation of interstrand crosslink DNA damage. Thus, NBS1 has multifunctional roles in response to DNA damage from a variety of genotoxic agents, including IR. Full article
(This article belongs to the Special Issue DNA Damage Response)
Open AccessReview Targeting the Checkpoint to Kill Cancer Cells
Biomolecules 2015, 5(3), 1912-1937; doi:10.3390/biom5031912
Received: 2 July 2015 / Revised: 7 August 2015 / Accepted: 11 August 2015 / Published: 18 August 2015
Cited by 13 | PDF Full-text (1370 KB) | HTML Full-text | XML Full-text
Abstract
Cancer treatments such as radiotherapy and most of the chemotherapies act by damaging DNA of cancer cells. Upon DNA damage, cells stop proliferation at cell cycle checkpoints, which provides them time for DNA repair. Inhibiting the checkpoint allows entry to mitosis despite the
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Cancer treatments such as radiotherapy and most of the chemotherapies act by damaging DNA of cancer cells. Upon DNA damage, cells stop proliferation at cell cycle checkpoints, which provides them time for DNA repair. Inhibiting the checkpoint allows entry to mitosis despite the presence of DNA damage and can lead to cell death. Importantly, as cancer cells exhibit increased levels of endogenous DNA damage due to an excessive replication stress, inhibiting the checkpoint kinases alone could act as a directed anti-cancer therapy. Here, we review the current status of inhibitors targeted towards the checkpoint effectors and discuss mechanisms of their actions in killing of cancer cells. Full article
(This article belongs to the Special Issue DNA Damage Response)
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Open AccessReview Genome Instability in Development and Aging: Insights from Nucleotide Excision Repair in Humans, Mice, and Worms
Biomolecules 2015, 5(3), 1855-1869; doi:10.3390/biom5031855
Received: 16 July 2015 / Revised: 6 August 2015 / Accepted: 7 August 2015 / Published: 13 August 2015
Cited by 4 | PDF Full-text (12295 KB) | HTML Full-text | XML Full-text
Abstract
DNA damage causally contributes to aging and cancer. Congenital defects in nucleotide excision repair (NER) lead to distinct cancer-prone and premature aging syndromes. The genetics of NER mutations have provided important insights into the distinct consequences of genome instability. Recent work in mice
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DNA damage causally contributes to aging and cancer. Congenital defects in nucleotide excision repair (NER) lead to distinct cancer-prone and premature aging syndromes. The genetics of NER mutations have provided important insights into the distinct consequences of genome instability. Recent work in mice and C. elegans has shed new light on the mechanisms through which developing and aging animals respond to persistent DNA damage. The various NER mouse mutants have served as important disease models for Xeroderma pigmentosum (XP), Cockayne syndrome (CS), and trichothiodystrophy (TTD), while the traceable genetics of C. elegans have allowed the mechanistic delineation of the distinct outcomes of genome instability in metazoan development and aging. Intriguingly, highly conserved longevity assurance mechanisms respond to transcription-blocking DNA lesions in mammals as well as in worms and counteract the detrimental consequences of persistent DNA damage. The insulin-like growth factor signaling (IIS) effector transcription factor DAF-16 could indeed overcome DNA damage-driven developmental growth delay and functional deterioration even when DNA damage persists. Longevity assurance mechanisms might thus delay DNA damage-driven aging by raising the threshold when accumulating DNA damage becomes detrimental for physiological tissue functioning. Full article
(This article belongs to the Special Issue DNA Damage Response)
Open AccessReview Bacterial Genotoxins: Merging the DNA Damage Response into Infection Biology
Biomolecules 2015, 5(3), 1762-1782; doi:10.3390/biom5031762
Received: 14 July 2015 / Revised: 5 August 2015 / Accepted: 6 August 2015 / Published: 11 August 2015
Cited by 3 | PDF Full-text (1826 KB) | HTML Full-text | XML Full-text
Abstract
Bacterial genotoxins are unique among bacterial toxins as their molecular target is DNA. The consequence of intoxication or infection is induction of DNA breaks that, if not properly repaired, results in irreversible cell cycle arrest (senescence) or death of the target cells. At
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Bacterial genotoxins are unique among bacterial toxins as their molecular target is DNA. The consequence of intoxication or infection is induction of DNA breaks that, if not properly repaired, results in irreversible cell cycle arrest (senescence) or death of the target cells. At present, only three bacterial genotoxins have been identified. Two are protein toxins: the cytolethal distending toxin (CDT) family produced by a number of Gram-negative bacteria and the typhoid toxin produced by Salmonella enterica serovar Typhi. The third member, colibactin, is a peptide-polyketide genotoxin, produced by strains belonging to the phylogenetic group B2 of Escherichia coli. This review will present the cellular effects of acute and chronic intoxication or infection with the genotoxins-producing bacteria. The carcinogenic properties and the role of these effectors in the context of the host-microbe interaction will be discussed. We will further highlight the open questions that remain to be solved regarding the biology of this unusual family of bacterial toxins. Full article
(This article belongs to the Special Issue DNA Damage Response)
Open AccessReview Inhibition of Topoisomerase (DNA) I (TOP1): DNA Damage Repair and Anticancer Therapy
Biomolecules 2015, 5(3), 1652-1670; doi:10.3390/biom5031652
Received: 22 May 2015 / Accepted: 14 July 2015 / Published: 22 July 2015
Cited by 14 | PDF Full-text (636 KB) | HTML Full-text | XML Full-text
Abstract
Most chemotherapy regimens contain at least one DNA-damaging agent that preferentially affects the growth of cancer cells. This strategy takes advantage of the differences in cell proliferation between normal and cancer cells. Chemotherapeutic drugs are usually designed to target rapid-dividing cells because sustained
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Most chemotherapy regimens contain at least one DNA-damaging agent that preferentially affects the growth of cancer cells. This strategy takes advantage of the differences in cell proliferation between normal and cancer cells. Chemotherapeutic drugs are usually designed to target rapid-dividing cells because sustained proliferation is a common feature of cancer [1,2]. Rapid DNA replication is essential for highly proliferative cells, thus blocking of DNA replication will create numerous mutations and/or chromosome rearrangements—ultimately triggering cell death [3]. Along these lines, DNA topoisomerase inhibitors are of great interest because they help to maintain strand breaks generated by topoisomerases during replication. In this article, we discuss the characteristics of topoisomerase (DNA) I (TOP1) and its inhibitors, as well as the underlying DNA repair pathways and the use of TOP1 inhibitors in cancer therapy. Full article
(This article belongs to the Special Issue DNA Damage Response)
Open AccessReview Transcription Blockage Leads to New Beginnings
Biomolecules 2015, 5(3), 1600-1617; doi:10.3390/biom5031600
Received: 23 June 2015 / Revised: 9 July 2015 / Accepted: 16 July 2015 / Published: 21 July 2015
Cited by 2 | PDF Full-text (2071 KB) | HTML Full-text | XML Full-text
Abstract
Environmental agents are constantly challenging cells by damaging DNA, leading to the blockage of transcription elongation. How do cells deal with transcription-blockage and how is transcription restarted after the blocking lesions are removed? Here we review the processes responsible for the removal of
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Environmental agents are constantly challenging cells by damaging DNA, leading to the blockage of transcription elongation. How do cells deal with transcription-blockage and how is transcription restarted after the blocking lesions are removed? Here we review the processes responsible for the removal of transcription-blocking lesions, as well as mechanisms of transcription restart. We also discuss recent data suggesting that blocked RNA polymerases may not resume transcription from the site of the lesion following its removal but, rather, are forced to start over from the beginning of genes. Full article
(This article belongs to the Special Issue DNA Damage Response)
Open AccessReview Protein Degradation Pathways Regulate the Functions of Helicases in the DNA Damage Response and Maintenance of Genomic Stability
Biomolecules 2015, 5(2), 590-616; doi:10.3390/biom5020590
Received: 25 February 2015 / Revised: 9 April 2015 / Accepted: 13 April 2015 / Published: 21 April 2015
Cited by 4 | PDF Full-text (5311 KB) | HTML Full-text | XML Full-text
Abstract
Degradation of helicases or helicase-like proteins, often mediated by ubiquitin-proteasomal pathways, plays important regulatory roles in cellular mechanisms that respond to DNA damage or replication stress. The Bloom’s syndrome helicase (BLM) provides an example of how helicase degradation pathways, regulated by post-translational modifications
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Degradation of helicases or helicase-like proteins, often mediated by ubiquitin-proteasomal pathways, plays important regulatory roles in cellular mechanisms that respond to DNA damage or replication stress. The Bloom’s syndrome helicase (BLM) provides an example of how helicase degradation pathways, regulated by post-translational modifications and protein interactions with components of the Fanconi Anemia (FA) interstrand cross-link (ICL) repair pathway, influence cell cycle checkpoints, DNA repair, and replication restart. The FANCM DNA translocase can be targeted by checkpoint kinases that exert dramatic effects on FANCM stability and chromosomal integrity. Other work provides evidence that degradation of the F-box DNA helicase (FBH1) helps to balance translesion synthesis (TLS) and homologous recombination (HR) repair at blocked replication forks. Degradation of the helicase-like transcription factor (HLTF), a DNA translocase and ubiquitylating enzyme, influences the choice of post replication repair (PRR) pathway. Stability of the Werner syndrome helicase-nuclease (WRN) involved in the replication stress response is regulated by its acetylation. Turning to transcription, stability of the Cockayne Syndrome Group B DNA translocase (CSB) implicated in transcription-coupled repair (TCR) is regulated by a CSA ubiquitin ligase complex enabling recovery of RNA synthesis. Collectively, these studies demonstrate that helicases can be targeted for degradation to maintain genome homeostasis. Full article
(This article belongs to the Special Issue DNA Damage Response)
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Open AccessReview Role of the Checkpoint Clamp in DNA Damage Response
Biomolecules 2013, 3(1), 75-84; doi:10.3390/biom3010075
Received: 3 December 2012 / Revised: 9 January 2013 / Accepted: 10 January 2013 / Published: 16 January 2013
Cited by 3 | PDF Full-text (397 KB) | HTML Full-text | XML Full-text
Abstract
DNA damage occurs during DNA replication, spontaneous chemical reactions, and assaults by external or metabolism-derived agents. Therefore, all living cells must constantly contend with DNA damage. Cells protect themselves from these genotoxic stresses by activating the DNA damage checkpoint and DNA repair pathways.
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DNA damage occurs during DNA replication, spontaneous chemical reactions, and assaults by external or metabolism-derived agents. Therefore, all living cells must constantly contend with DNA damage. Cells protect themselves from these genotoxic stresses by activating the DNA damage checkpoint and DNA repair pathways. Coordination of these pathways requires tight regulation in order to prevent genomic instability. The checkpoint clamp complex consists of Rad9, Rad1 and Hus1 proteins, and is often called the 9-1-1 complex. This PCNA (proliferating cell nuclear antigen)-like donut-shaped protein complex is a checkpoint sensor protein that is recruited to DNA damage sites during the early stage of the response, and is required for checkpoint activation. As PCNA is required for multiple pathways of DNA metabolism, the checkpoint clamp has also been implicated in direct roles in DNA repair, as well as in coordination of the pathways. Here we discuss roles of the checkpoint clamp in DNA damage response (DDR). Full article
(This article belongs to the Special Issue DNA Damage Response)
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Open AccessReview Homologous Recombination as a Replication Fork Escort: Fork-Protection and Recovery
Biomolecules 2013, 3(1), 39-71; doi:10.3390/biom3010039
Received: 30 October 2012 / Revised: 11 December 2012 / Accepted: 11 December 2012 / Published: 27 December 2012
Cited by 12 | PDF Full-text (829 KB) | HTML Full-text | XML Full-text
Abstract
Homologous recombination is a universal mechanism that allows DNA repair and ensures the efficiency of DNA replication. The substrate initiating the process of homologous recombination is a single-stranded DNA that promotes a strand exchange reaction resulting in a genetic exchange that promotes genetic
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Homologous recombination is a universal mechanism that allows DNA repair and ensures the efficiency of DNA replication. The substrate initiating the process of homologous recombination is a single-stranded DNA that promotes a strand exchange reaction resulting in a genetic exchange that promotes genetic diversity and DNA repair. The molecular mechanisms by which homologous recombination repairs a double-strand break have been extensively studied and are now well characterized. However, the mechanisms by which homologous recombination contribute to DNA replication in eukaryotes remains poorly understood. Studies in bacteria have identified multiple roles for the machinery of homologous recombination at replication forks. Here, we review our understanding of the molecular pathways involving the homologous recombination machinery to support the robustness of DNA replication. In addition to its role in fork-recovery and in rebuilding a functional replication fork apparatus, homologous recombination may also act as a fork-protection mechanism. We discuss that some of the fork-escort functions of homologous recombination might be achieved by loading of the recombination machinery at inactivated forks without a need for a strand exchange step; as well as the consequence of such a model for the stability of eukaryotic genomes. Full article
(This article belongs to the Special Issue DNA Damage Response)
Open AccessReview Molecular Insights into Poly(ADP-ribose) Recognition and Processing
Biomolecules 2013, 3(1), 1-17; doi:10.3390/biom3010001
Received: 24 October 2012 / Revised: 1 December 2012 / Accepted: 17 December 2012 / Published: 21 December 2012
Cited by 13 | PDF Full-text (414 KB) | HTML Full-text | XML Full-text
Abstract
Poly(ADP-ribosyl)ation is a post-translational protein modification involved in the regulation of important cellular functions including DNA repair, transcription, mitosis and apoptosis. The amount of poly(ADP-ribosyl)ation (PAR) in cells reflects the balance of synthesis, mediated by the PARP protein family, and degradation, which is
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Poly(ADP-ribosyl)ation is a post-translational protein modification involved in the regulation of important cellular functions including DNA repair, transcription, mitosis and apoptosis. The amount of poly(ADP-ribosyl)ation (PAR) in cells reflects the balance of synthesis, mediated by the PARP protein family, and degradation, which is catalyzed by a glycohydrolase, PARG. Many of the proteins mediating PAR metabolism possess specialised high affinity PAR-binding modules that allow the efficient sensing or processing of the PAR signal. The identification of four such PAR-binding modules and the characterization of a number of proteins utilising these elements during the last decade has provided important insights into how PAR regulates different cellular activities. The macrodomain represents a unique PAR-binding module which is, in some instances, known to possess enzymatic activity on ADP-ribose derivatives (in addition to PAR-binding). The most recently discovered example for this is the PARG protein, and several available PARG structures have provided an understanding into how the PARG macrodomain evolved into a major enzyme that maintains PAR homeostasis in living cells. Full article
(This article belongs to the Special Issue DNA Damage Response)
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Open AccessReview Strategies for the Use of Poly(adenosine diphosphate ribose) Polymerase (PARP) Inhibitors in Cancer Therapy
Biomolecules 2012, 2(4), 635-649; doi:10.3390/biom2040635
Received: 12 October 2012 / Revised: 29 November 2012 / Accepted: 9 December 2012 / Published: 14 December 2012
Cited by 7 | PDF Full-text (455 KB) | HTML Full-text | XML Full-text
Abstract
Treatments with Poly(adenosine diphosphate ribose) polymerase (PARP) inhibitors have offered patients carrying cancers with mutated BRCA1 or BRCA2 genes a new and in many cases effective option for disease control. There is potentially a large patient population that may also benefit from PARP
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Treatments with Poly(adenosine diphosphate ribose) polymerase (PARP) inhibitors have offered patients carrying cancers with mutated BRCA1 or BRCA2 genes a new and in many cases effective option for disease control. There is potentially a large patient population that may also benefit from PARP inhibitor treatment, either in monotherapy or in combination with chemotherapy. Here, we describe the multifaceted role of PARP inhibitors and discuss which treatment options could potentially be useful to gain disease control without potentiating side effects. Full article
(This article belongs to the Special Issue DNA Damage Response)
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Open AccessReview Pathways for Genome Integrity in G2 Phase of the Cell Cycle
Biomolecules 2012, 2(4), 579-607; doi:10.3390/biom2040579
Received: 17 October 2012 / Revised: 17 November 2012 / Accepted: 23 November 2012 / Published: 30 November 2012
Cited by 4 | PDF Full-text (517 KB) | HTML Full-text | XML Full-text | Correction | Supplementary Files
Abstract
The maintenance of genome integrity is important for normal cellular functions, organism development and the prevention of diseases, such as cancer. Cellular pathways respond immediately to DNA breaks leading to the initiation of a multi-facetted DNA damage response, which leads to DNA repair
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The maintenance of genome integrity is important for normal cellular functions, organism development and the prevention of diseases, such as cancer. Cellular pathways respond immediately to DNA breaks leading to the initiation of a multi-facetted DNA damage response, which leads to DNA repair and cell cycle arrest. Cell cycle checkpoints provide the cell time to complete replication and repair the DNA damage before it can continue to the next cell cycle phase. The G2/M checkpoint plays an especially important role in ensuring the propagation of error-free copies of the genome to each daughter cell. Here, we review recent progress in our understanding of DNA repair and checkpoint pathways in late S and G2 phases. This review will first describe the current understanding of normal cell cycle progression through G2 phase to mitosis. It will also discuss the DNA damage response including cell cycle checkpoint control and DNA double-strand break repair. Finally, we discuss the emerging concept that DNA repair pathways play a major role in the G2/M checkpoint pathway thereby blocking cell division as long as DNA lesions are present. Full article
(This article belongs to the Special Issue DNA Damage Response)
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Open AccessReview Functional Aspects of PARP1 in DNA Repair and Transcription
Biomolecules 2012, 2(4), 524-548; doi:10.3390/biom2040524
Received: 18 September 2012 / Revised: 24 October 2012 / Accepted: 31 October 2012 / Published: 12 November 2012
Cited by 13 | PDF Full-text (594 KB) | HTML Full-text | XML Full-text
Abstract
Poly (ADP-ribose) polymerase 1 (PARP1) is an ADP-ribosylating enzyme essential for initiating various forms of DNA repair. Inhibiting its enzyme activity with small molecules thus achieves synthetic lethality by preventing unwanted DNA repair in the treatment of cancers. Through enzyme-dependent chromatin remodeling and
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Poly (ADP-ribose) polymerase 1 (PARP1) is an ADP-ribosylating enzyme essential for initiating various forms of DNA repair. Inhibiting its enzyme activity with small molecules thus achieves synthetic lethality by preventing unwanted DNA repair in the treatment of cancers. Through enzyme-dependent chromatin remodeling and enzyme-independent motif recognition, PARP1 also plays important roles in regulating gene expression. Besides presenting current findings on how each process is individually controlled by PARP1, we shall discuss how transcription and DNA repair are so intricately linked that disturbance by PARP1 enzymatic inhibition, enzyme hyperactivation in diseases, and viral replication can favor one function while suppressing the other. Full article
(This article belongs to the Special Issue DNA Damage Response)
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Open AccessReview Preserving Yeast Genetic Heritage through DNA Damage Checkpoint Regulation and Telomere Maintenance
Biomolecules 2012, 2(4), 505-523; doi:10.3390/biom2040505
Received: 10 September 2012 / Revised: 10 October 2012 / Accepted: 22 October 2012 / Published: 30 October 2012
PDF Full-text (538 KB) | HTML Full-text | XML Full-text
Abstract
In order to preserve genome integrity, extrinsic or intrinsic DNA damages must be repaired before they accumulate in cells and trigger other mutations and genome rearrangements. Eukaryotic cells are able to respond to different genotoxic stresses as well as to single DNA double
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In order to preserve genome integrity, extrinsic or intrinsic DNA damages must be repaired before they accumulate in cells and trigger other mutations and genome rearrangements. Eukaryotic cells are able to respond to different genotoxic stresses as well as to single DNA double strand breaks (DSBs), suggesting highly sensitive and robust mechanisms to detect lesions that trigger a signal transduction cascade which, in turn, controls the DNA damage response (DDR). Furthermore, cells must be able to distinguish natural chromosomal ends from DNA DSBs in order to prevent inappropriate checkpoint activation, DDR and chromosomal rearrangements. Since the original discovery of RAD9, the first DNA damage checkpoint gene identified in Saccharomyces cerevisiae, many genes that have a role in this pathway have been identified, including MRC1, MEC3, RAD24, RAD53, DUN1, MEC1 and TEL1. Extensive studies have established most of the genetic basis of the DNA damage checkpoint and uncovered its different functions in cell cycle regulation, DNA replication and repair, and telomere maintenance. However, major questions concerning the regulation and functions of the DNA damage checkpoint remain to be answered. First, how is the checkpoint activity coupled to DNA replication and repair? Second, how do cells distinguish natural chromosome ends from deleterious DNA DSBs? In this review we will examine primarily studies performed using Saccharomyces cerevisiae as a model system. Full article
(This article belongs to the Special Issue DNA Damage Response)
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Open AccessReview Break-Induced Replication and Genome Stability
Biomolecules 2012, 2(4), 483-504; doi:10.3390/biom2040483
Received: 10 August 2012 / Revised: 5 October 2012 / Accepted: 8 October 2012 / Published: 16 October 2012
Cited by 8 | PDF Full-text (642 KB) | HTML Full-text | XML Full-text
Abstract
Genetic instabilities, including mutations and chromosomal rearrangements, lead to cancer and other diseases in humans and play an important role in evolution. A frequent cause of genetic instabilities is double-strand DNA breaks (DSBs), which may arise from a wide range of exogeneous and
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Genetic instabilities, including mutations and chromosomal rearrangements, lead to cancer and other diseases in humans and play an important role in evolution. A frequent cause of genetic instabilities is double-strand DNA breaks (DSBs), which may arise from a wide range of exogeneous and endogeneous cellular factors. Although the repair of DSBs is required, some repair pathways are dangerous because they may destabilize the genome. One such pathway, break-induced replication (BIR), is the mechanism for repairing DSBs that possesses only one repairable end. This situation commonly arises as a result of eroded telomeres or collapsed replication forks. Although BIR plays a positive role in repairing DSBs, it can alternatively be a dangerous source of several types of genetic instabilities, including loss of heterozygosity, telomere maintenance in the absence of telomerase, and non-reciprocal translocations. Also, mutation rates in BIR are about 1000 times higher as compared to normal DNA replication. In addition, micro-homology-mediated BIR (MMBIR), which is a mechanism related to BIR, can generate copy-number variations (CNVs) as well as various complex chromosomal rearrangements. Overall, activation of BIR may contribute to genomic destabilization resulting in substantial biological consequences including those affecting human health. Full article
(This article belongs to the Special Issue DNA Damage Response)
Open AccessReview Sumoylation and the DNA Damage Response
Biomolecules 2012, 2(3), 376-388; doi:10.3390/biom2030376
Received: 1 August 2012 / Revised: 23 August 2012 / Accepted: 24 August 2012 / Published: 4 September 2012
Cited by 7 | PDF Full-text (680 KB) | HTML Full-text | XML Full-text
Abstract
The cellular response to DNA damage involves multiple pathways that work together to promote survival in the face of increased genotoxic lesions. Proteins in these pathways are often posttranslationally modified, either by small groups such as phosphate, or by protein modifiers such as
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The cellular response to DNA damage involves multiple pathways that work together to promote survival in the face of increased genotoxic lesions. Proteins in these pathways are often posttranslationally modified, either by small groups such as phosphate, or by protein modifiers such as ubiquitin or SUMO. The recent discovery of many more SUMO substrates that are modified at higher levels in damage conditions adds weight to the accumulated evidence suggesting that sumoylation plays an important functional role in the DNA damage response. Here we discuss the significance of DNA damage-induced sumoylation, the effects of sumoylation on repair proteins, sumoylation dynamics, and crosstalk with other posttranslational modifications in the DNA damage response. Full article
(This article belongs to the Special Issue DNA Damage Response)
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Open AccessCorrection Correction: Pennisi, R., et al. Hsp90: A New Player in DNA Repair? Biomolecules 2015, 5, 2589–2618
Biomolecules 2016, 6(4), 40; doi:10.3390/biom6040040
Received: 14 September 2016 / Accepted: 14 September 2016 / Published: 18 October 2016
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(This article belongs to the Special Issue DNA Damage Response)

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