ijms-logo

Journal Browser

Journal Browser

Special Issue "DNA Injury and Repair Systems"

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (31 July 2017).

Special Issue Editor

Guest Editor
Prof. Guillermo T. Sáez E-Mail
Department of Biochemistry and Molecular Biology, Faculty of Medicine and Odontology-INCLIVA, Service of Clinical Analysis, University Hospital Dr. Peset, University of Valencia, Avda. Blasco Ibañez 15, Valencia, Spain
Phone: +34 963864160
Fax: +34 96 386 4101
Interests: Oxidative stress-induced DNA damage and repair and its repair mechanisms in cardiometabolic and cancer diseases.

Special Issue Information

Dear Colleagues,

The integrity of the structure and composition of nucleic acids is a fundamental requirement, not only to ensure fidelity in the transmission of the genetic message, but also to preserve the metabolic regulation and physiological functions of living organisms. However, the genetic material is exposed to multiple exogenous and endogenous sources that modify its structure through different interaction mechanisms. Some of these modifications play regulatory roles necessary for the control of cell growth and differentiation while others are detrimental for their survival.

Ionizing, neutron or UV radiations, the interaction with chemical agents and prooxidants, in addition to many other environmental factors, are major sources of DNA lesions. Some of these agents have proved to be very useful in the treatment of tumor diseases. However, the modification and damage to DNA is a well-known mechanism of spontaneous mutations leading to sporadic cancer.

It is deduced that the cells have evolved thanks to their ability to escape from the harmful impacts on its DNA structure trying to maintain a balance between the processes of regulatory modifications and those that endanger their viability and biological functions. This ability lies on the DNA repair systems, which have been conserved along the phylogenetic scale. DNA repair is of vital importance and its effectiveness is ensured by a complex process of molecular signaling and interactions involving multiple and sophisticated groups of proteins including transcriptional factors, and tumor suppressor genes working in an orchestrated manner with a specific repair enzymes.

The repair of the genetic material encompasses each and every one of its different damaging forms. Inefficiency of one or more of these repair proteins have been related with the abnormal regulation of apoptosis and cellular senescence, therefore contributing to the development of degenerative diseases.

In this Special Issue, special attention will be focused on the different agents and mechanisms responsible for the modification of genetic material, as well as repair systems as essential biological factors for the maintenance of cell homeostasis.

Prof. Guillermo T. Sáez
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Radiation
  • chemicals
  • DNA modification and damage
  • oxidative damage
  • DNA repair mechanisms
  • disease

Published Papers (14 papers)

Order results
Result details
Select all
Export citation of selected articles as:

Editorial

Jump to: Research, Review

Open AccessEditorial
DNA Injury and Repair Systems
Int. J. Mol. Sci. 2018, 19(7), 1902; https://doi.org/10.3390/ijms19071902 - 28 Jun 2018
(This article belongs to the Special Issue DNA Injury and Repair Systems)

Research

Jump to: Editorial, Review

Open AccessArticle
Reverse Gyrase Functions in Genome Integrity Maintenance by Protecting DNA Breaks In Vivo
Int. J. Mol. Sci. 2017, 18(7), 1340; https://doi.org/10.3390/ijms18071340 - 22 Jun 2017
Cited by 6
Abstract
Reverse gyrase introduces positive supercoils to circular DNA and is implicated in genome stability maintenance in thermophiles. The extremely thermophilic crenarchaeon Sulfolobus encodes two reverse gyrase proteins, TopR1 (topoisomerase reverse gyrase 1) and TopR2, whose functions in thermophilic life remain to be demonstrated. [...] Read more.
Reverse gyrase introduces positive supercoils to circular DNA and is implicated in genome stability maintenance in thermophiles. The extremely thermophilic crenarchaeon Sulfolobus encodes two reverse gyrase proteins, TopR1 (topoisomerase reverse gyrase 1) and TopR2, whose functions in thermophilic life remain to be demonstrated. Here, we investigated the roles of TopR1 in genome stability maintenance in S. islandicus in response to the treatment of methyl methanesulfonate (MMS), a DNA alkylation agent. Lethal MMS treatment induced two successive events: massive chromosomal DNA backbone breakage and subsequent DNA degradation. The former occurred immediately after drug treatment, leading to chromosomal DNA degradation that concurred with TopR1 degradation, followed by chromatin protein degradation and DNA-less cell formation. To gain a further insight into TopR1 function, the expression of the enzyme was reduced in S. islandicus cells using a CRISPR-mediated mRNA interference approach (CRISPRi) in which topR1 mRNAs were targeted for degradation by endogenous III-B CRISPR-Cas systems. We found that the TopR1 level was reduced in the S. islandicus CRISPRi cells and that the cells underwent accelerated genomic DNA degradation during MMS treatment, accompanied by a higher rate of cell death. Taken together, these results indicate that TopR1 probably facilitates genome integrity maintenance by protecting DNA breaks from thermo-degradation in vivo. Full article
(This article belongs to the Special Issue DNA Injury and Repair Systems)
Show Figures

Graphical abstract

Open AccessArticle
Dynamic In Vivo Profiling of DNA Damage and Repair after Radiotherapy Using Canine Patients as a Model
Int. J. Mol. Sci. 2017, 18(6), 1176; https://doi.org/10.3390/ijms18061176 - 01 Jun 2017
Cited by 4
Abstract
Time resolved data of DNA damage and repair after radiotherapy elucidates the relation between damage, repair, and cell survival. While well characterized in vitro, little is known about the time-course of DNA damage response in tumors sampled from individual patients. Kinetics of DNA [...] Read more.
Time resolved data of DNA damage and repair after radiotherapy elucidates the relation between damage, repair, and cell survival. While well characterized in vitro, little is known about the time-course of DNA damage response in tumors sampled from individual patients. Kinetics of DNA damage after radiotherapy was assessed in eight dogs using repeated in vivo samples of tumor and co-irradiated normal tissue analyzed with comet assay and phosphorylated H2AX (γH2AX) immunohistochemistry. In vivo results were then compared (in silico) with a dynamic mathematical model for DNA damage formation and repair. Maximum %DNA in tail was observed at 15–60 min after irradiation, with a rapid decrease. Time-courses of γH2AX-foci paralleled these findings with a small time delay and were not influenced by covariates. The evolutionary parameter search based on %DNA in tail revealed a good fit of the DNA repair model to in vivo data for pooled sarcoma time-courses, but fits for individual sarcoma time-courses suffer from the heterogeneous nature of the in vivo data. It was possible to follow dynamics of comet tail intensity and γH2AX-foci during a course of radiation using a minimally invasive approach. DNA repair can be quantitatively investigated as time-courses of individual patients by integrating this resulting data into a dynamic mathematical model. Full article
(This article belongs to the Special Issue DNA Injury and Repair Systems)
Show Figures

Graphical abstract

Open AccessArticle
Microvesicles Contribute to the Bystander Effect of DNA Damage
Int. J. Mol. Sci. 2017, 18(4), 788; https://doi.org/10.3390/ijms18040788 - 07 Apr 2017
Cited by 3
Abstract
Genotoxic treatments elicit DNA damage response (DDR) not only in cells that are directly exposed but also in cells that are not in the field of treatment (bystander cells), a phenomenon that is commonly referred to as the bystander effect (BE). However, mechanisms [...] Read more.
Genotoxic treatments elicit DNA damage response (DDR) not only in cells that are directly exposed but also in cells that are not in the field of treatment (bystander cells), a phenomenon that is commonly referred to as the bystander effect (BE). However, mechanisms underlying the BE remain elusive. We report here that etoposide and ultraviolet (UV) exposure stimulate the production of microvesicles (MVs) in DU145 prostate cancer cells. MVs isolated from UV-treated DU145 and A431 epidermoid carcinoma cells as well as etoposide-treated DU145 cells induced phosphorylation of ataxia-telangiectasia mutated (ATM) at serine 1981 (indicative of ATM activation) and phosphorylation of histone H2AX at serine 139 (γH2AX) in naïve DU145 cells. Importantly, neutralization of MVs derived from UV-treated cells with annexin V significantly reduced the MV-associated BE activities. Etoposide and UV are known to induce DDR primarily through the ATM and ATM- and Rad3-related (ATR) pathways, respectively. In this regard, MV is likely a common source for the DNA damage-induced bystander effect. However, pre-treatment of DU145 naïve cells with an ATM (KU55933) inhibitor does not affect the BE elicited by MVs isolated from etoposide-treated cells, indicating that the BE is induced upstream of ATM actions. Taken together, we provide evidence supporting that MVs are a source of the DNA damage-induced bystander effect. Full article
(This article belongs to the Special Issue DNA Injury and Repair Systems)
Show Figures

Graphical abstract

Review

Jump to: Editorial, Research

Open AccessReview
Around and beyond 53BP1 Nuclear Bodies
Int. J. Mol. Sci. 2017, 18(12), 2611; https://doi.org/10.3390/ijms18122611 - 05 Dec 2017
Cited by 12
Abstract
Within the nucleus, sub-nuclear domains define territories where specific functions occur. Nuclear bodies (NBs) are dynamic structures that concentrate nuclear factors and that can be observed microscopically. Recently, NBs containing the p53 binding protein 1 (53BP1), a key component of the DNA damage [...] Read more.
Within the nucleus, sub-nuclear domains define territories where specific functions occur. Nuclear bodies (NBs) are dynamic structures that concentrate nuclear factors and that can be observed microscopically. Recently, NBs containing the p53 binding protein 1 (53BP1), a key component of the DNA damage response, were defined. Interestingly, 53BP1 NBs are visualized during G1 phase, in daughter cells, while DNA damage was generated in mother cells and not properly processed. Unlike most NBs involved in transcriptional processes, replication has proven to be key for 53BP1 NBs, with replication stress leading to the formation of these large chromatin domains in daughter cells. In this review, we expose the composition and organization of 53BP1 NBs and focus on recent findings regarding their regulation and dynamics. We then concentrate on the importance of the replication stress, examine the relation of 53BP1 NBs with DNA damage and discuss their dysfunction. Full article
(This article belongs to the Special Issue DNA Injury and Repair Systems)
Show Figures

Graphical abstract

Open AccessReview
DNA Adducts Formed by Aristolochic Acid Are Unique Biomarkers of Exposure and Explain the Initiation Phase of Upper Urothelial Cancer
Int. J. Mol. Sci. 2017, 18(10), 2144; https://doi.org/10.3390/ijms18102144 - 14 Oct 2017
Cited by 14
Abstract
Aristolochic acid (AA) is a plant alkaloid that causes aristolochic acid nephropathy (AAN) and Balkan endemic nephropathy (BEN), unique renal diseases frequently associated with upper urothelial cancer (UUC). This review summarizes the significance of AA-derived DNA adducts in the aetiology of UUC leading [...] Read more.
Aristolochic acid (AA) is a plant alkaloid that causes aristolochic acid nephropathy (AAN) and Balkan endemic nephropathy (BEN), unique renal diseases frequently associated with upper urothelial cancer (UUC). This review summarizes the significance of AA-derived DNA adducts in the aetiology of UUC leading to specific A:T to T:A transversion mutations (mutational signature) in AAN/BEN-associated tumours, which are otherwise rare in individuals with UCC not exposed to AA. Therefore, such DNA damage produced by AA-DNA adducts is one rare example of the direct association of exposure and cancer development (UUC) in humans, confirming that the covalent binding of carcinogens to DNA is causally related to tumourigenesis. Although aristolochic acid I (AAI), the major component of the natural plant extract AA, might directly cause interstitial nephropathy, enzymatic activation of AAI to reactive intermediates capable of binding to DNA is a necessary step leading to the formation of AA-DNA adducts and subsequently AA-induced malignant transformation. Therefore, AA-DNA adducts can not only be utilized as biomarkers for the assessment of AA exposure and markers of AA-induced UUC, but also be used for the mechanistic evaluation of its enzymatic activation and detoxification. Differences in AA metabolism might be one of the reasons for an individual’s susceptibility in the multi-step process of AA carcinogenesis and studying associations between activities and/or polymorphisms of the enzymes metabolising AA is an important determinant to identify individuals having a high risk of developing AA-mediated UUC. Full article
(This article belongs to the Special Issue DNA Injury and Repair Systems)
Show Figures

Graphical abstract

Open AccessReview
Induced Pluripotent Stem Cells: Advances in the Quest for Genetic Stability during Reprogramming Process
Int. J. Mol. Sci. 2017, 18(9), 1952; https://doi.org/10.3390/ijms18091952 - 13 Sep 2017
Cited by 9
Abstract
Evaluation of the extent and nature of induced pluripotent stem cell (iPSC) genetic instability is important for both basic research and future clinical use. As previously demonstrated regarding embryonic stem cells, such DNA aberrations might affect the differentiation capacity of the cells and [...] Read more.
Evaluation of the extent and nature of induced pluripotent stem cell (iPSC) genetic instability is important for both basic research and future clinical use. As previously demonstrated regarding embryonic stem cells, such DNA aberrations might affect the differentiation capacity of the cells and increase their tumorigenicity. Here, we first focus on the contribution of multiple DNA damage response pathways during cellular reprogramming. We then discuss the origin and mechanisms responsible for the modification of genetic material in iPSCs (pre-existing variations in somatic cells, mutations induced by reprogramming factors, and mutations induced by culture expansion) and deepen the possible functional consequences of genetic variations in these cells. Lastly, we present some recent improvements of iPSC generation methods aimed at obtaining cells with fewer genetic variations. Full article
(This article belongs to the Special Issue DNA Injury and Repair Systems)
Show Figures

Figure 1

Open AccessReview
Molecular Mechanisms of Acetaldehyde-Mediated Carcinogenesis in Squamous Epithelium
Int. J. Mol. Sci. 2017, 18(9), 1943; https://doi.org/10.3390/ijms18091943 - 10 Sep 2017
Cited by 8
Abstract
Acetaldehyde is a highly reactive compound that causes various forms of damage to DNA, including DNA adducts, single- and/or double-strand breaks (DSBs), point mutations, sister chromatid exchanges (SCEs), and DNA–DNA cross-links. Among these, DNA adducts such as N2-ethylidene-2′-deoxyguanosine, N2-ethyl-2′-deoxyguanosine, [...] Read more.
Acetaldehyde is a highly reactive compound that causes various forms of damage to DNA, including DNA adducts, single- and/or double-strand breaks (DSBs), point mutations, sister chromatid exchanges (SCEs), and DNA–DNA cross-links. Among these, DNA adducts such as N2-ethylidene-2′-deoxyguanosine, N2-ethyl-2′-deoxyguanosine, N2-propano-2′-deoxyguanosine, and N2-etheno-2′-deoxyguanosine are central to acetaldehyde-mediated DNA damage because they are associated with the induction of DNA mutations, DNA–DNA cross-links, DSBs, and SCEs. Acetaldehyde is produced endogenously by alcohol metabolism and is catalyzed by aldehyde dehydrogenase 2 (ALDH2). Alcohol consumption increases blood and salivary acetaldehyde levels, especially in individuals with ALDH2 polymorphisms, which are highly associated with the risk of squamous cell carcinomas in the upper aerodigestive tract. Based on extensive epidemiological evidence, the International Agency for Research on Cancer defined acetaldehyde associated with the consumption of alcoholic beverages as a “group 1 carcinogen” (definite carcinogen) for the esophagus and/or head and neck. In this article, we review recent advances from studies of acetaldehyde-mediated carcinogenesis in the squamous epithelium, focusing especially on acetaldehyde-mediated DNA adducts. We also give attention to research on acetaldehyde-mediated DNA repair pathways such as the Fanconi anemia pathway and refer to our studies on the prevention of acetaldehyde-mediated DNA damage. Full article
(This article belongs to the Special Issue DNA Injury and Repair Systems)
Show Figures

Graphical abstract

Open AccessReview
The Role of PALB2 in the DNA Damage Response and Cancer Predisposition
Int. J. Mol. Sci. 2017, 18(9), 1886; https://doi.org/10.3390/ijms18091886 - 31 Aug 2017
Cited by 15
Abstract
The deoxyribonucleic acid (DNA) damage response (DDR) is a major feature in the maintenance of genome integrity and in the suppression of tumorigenesis. PALB2 (Partner and Localizer of Breast Cancer 2 (BRCA2)) plays an important role in maintaining genome integrity through its role [...] Read more.
The deoxyribonucleic acid (DNA) damage response (DDR) is a major feature in the maintenance of genome integrity and in the suppression of tumorigenesis. PALB2 (Partner and Localizer of Breast Cancer 2 (BRCA2)) plays an important role in maintaining genome integrity through its role in the Fanconi anemia (FA) and homologous recombination (HR) DNA repair pathways. Since its identification as a BRCA2 interacting partner, PALB2 has emerged as a pivotal tumor suppressor protein associated to hereditary cancer susceptibility to breast and pancreatic cancers. In this review, we discuss how other DDR proteins (such as the kinases Ataxia Telangiectasia Mutated (ATM) and ATM- and Rad3-Related (ATR), mediators BRCA1 (Breast Cancer 1)/BRCA2 and effectors RAD51/DNA Polymerase η (Polη) interact with PALB2 to orchestrate DNA repair. We also examine the involvement of PALB2 mutations in the predisposition to cancer and the role of PALB2 in stimulating error-free DNA repair through the FA/HR pathway. Full article
(This article belongs to the Special Issue DNA Injury and Repair Systems)
Show Figures

Graphical abstract

Open AccessReview
The Complex Interplay between DNA Injury and Repair in Enzymatically Induced Mutagenesis and DNA Damage in B Lymphocytes
Int. J. Mol. Sci. 2017, 18(9), 1876; https://doi.org/10.3390/ijms18091876 - 30 Aug 2017
Cited by 3
Abstract
Lymphocytes are endowed with unique and specialized enzymatic mutagenic properties that allow them to diversify their antigen receptors, which are crucial sensors for pathogens and mediators of adaptive immunity. During lymphocyte development, the antigen receptors expressed by B and T lymphocytes are assembled [...] Read more.
Lymphocytes are endowed with unique and specialized enzymatic mutagenic properties that allow them to diversify their antigen receptors, which are crucial sensors for pathogens and mediators of adaptive immunity. During lymphocyte development, the antigen receptors expressed by B and T lymphocytes are assembled in an antigen-independent fashion by ordered variable gene segment recombinations (V(D)J recombination), which is a highly ordered and regulated process that requires the recombination activating gene products 1 & 2 (RAG1, RAG2). Upon activation by antigen, B lymphocytes undergo additional diversifications of their immunoglobulin B-cell receptors. Enzymatically induced somatic hypermutation (SHM) and immunoglobulin class switch recombination (CSR) improves the affinity for antigen and shape the effector function of the humoral immune response, respectively. The activation-induced cytidine deaminase (AID) enzyme is crucial for both SHM and CSR. These processes have evolved to both utilize as well as evade different DNA repair and DNA damage response pathways. The delicate balance between enzymatic mutagenesis and DNA repair is crucial for effective immune responses and the maintenance of genomic integrity. Not surprisingly, disturbances in this balance are at the basis of lymphoid malignancies by provoking the formation of oncogenic mutations and chromosomal aberrations. In this review, we discuss recent mechanistic insight into the regulation of RAG1/2 and AID expression and activity in lymphocytes and the complex interplay between these mutagenic enzymes and DNA repair and DNA damage response pathways, focusing on the base excision repair and mismatch repair pathways. We discuss how disturbances of this interplay induce genomic instability and contribute to oncogenesis. Full article
(This article belongs to the Special Issue DNA Injury and Repair Systems)
Show Figures

Graphical abstract

Open AccessReview
The Emerging Role of GLP-1 Receptors in DNA Repair: Implications in Neurological Disorders
Int. J. Mol. Sci. 2017, 18(9), 1861; https://doi.org/10.3390/ijms18091861 - 26 Aug 2017
Cited by 3
Abstract
Glucagon-like peptide-1 (GLP-1) is originally found as a metabolic hormone (incretin) that is able to regulate blood-glucose levels via promoting synthesis and secretion of insulin. GLP-1 and many analogues are approved for treatment of type II diabetes. Accumulating results imply that GLP-1 performs [...] Read more.
Glucagon-like peptide-1 (GLP-1) is originally found as a metabolic hormone (incretin) that is able to regulate blood-glucose levels via promoting synthesis and secretion of insulin. GLP-1 and many analogues are approved for treatment of type II diabetes. Accumulating results imply that GLP-1 performs multiple functions in various tissues and organs beyond regulation of blood-glucose. The neuroprotective function of GLP-1 has been extensively explored during the past two decades. Three of our previous studies have shown that apurinic/apyrimidinic endonuclease 1 (APE1) is the only protein of the base excision repair (BER) pathway able to be regulated by oxidative stress or exogenous stimulations in rat primary cortical neurons. In this article, we review the role of APE1 in neurodegenerative diseases and its relationship to neuroprotective mechanisms of the activated GLP-1 receptor (GLP-1R) in neurodegenerative disorders. The purpose of this article is to provide new insight, from the aspect of DNA damage and repair, for studying potential treatments in neurodegenerative diseases. Full article
(This article belongs to the Special Issue DNA Injury and Repair Systems)
Show Figures

Graphical abstract

Open AccessReview
FANCD2 and DNA Damage
Int. J. Mol. Sci. 2017, 18(8), 1804; https://doi.org/10.3390/ijms18081804 - 19 Aug 2017
Cited by 6
Abstract
Investigators have dedicated considerable effort to understanding the molecular basis underlying Fanconi Anemia (FA), a rare human genetic disease featuring an extremely high incidence of cancer and many congenital defects. Among those studies, FA group D2 protein (FANCD2) has emerged as the focal [...] Read more.
Investigators have dedicated considerable effort to understanding the molecular basis underlying Fanconi Anemia (FA), a rare human genetic disease featuring an extremely high incidence of cancer and many congenital defects. Among those studies, FA group D2 protein (FANCD2) has emerged as the focal point of FA signaling and plays crucial roles in multiple aspects of cellular life, especially in the cellular responses to DNA damage. Here, we discuss the recent and relevant studies to provide an updated review on the roles of FANCD2 in the DNA damage response. Full article
(This article belongs to the Special Issue DNA Injury and Repair Systems)
Show Figures

Figure 1

Open AccessReview
Regulation of DNA Repair Mechanisms: How the Chromatin Environment Regulates the DNA Damage Response
Int. J. Mol. Sci. 2017, 18(8), 1715; https://doi.org/10.3390/ijms18081715 - 05 Aug 2017
Cited by 16
Abstract
Cellular DNA is constantly challenged by damage-inducing factors derived from exogenous or endogenous sources. In order to maintain genome stability and integrity, cells have evolved a wide variety of DNA repair pathways which counteract different types of DNA lesions, also referred to as [...] Read more.
Cellular DNA is constantly challenged by damage-inducing factors derived from exogenous or endogenous sources. In order to maintain genome stability and integrity, cells have evolved a wide variety of DNA repair pathways which counteract different types of DNA lesions, also referred to as the DNA damage response (DDR). However, DNA in eukaryotes is highly organized and compacted into chromatin representing major constraints for all cellular pathways, including DNA repair pathways, which require DNA as their substrate. Therefore, the chromatin configuration surrounding the lesion site undergoes dramatic remodeling to facilitate access of DNA repair factors and subsequent removal of the DNA lesion. In this review, we focus on the question of how the cellular DNA repair pathways overcome the chromatin barrier, how the chromatin environment is rearranged to facilitate efficient DNA repair, which proteins mediate this re-organization process and, consequently, how the altered chromatin landscape is involved in the regulation of DNA damage responses. Full article
(This article belongs to the Special Issue DNA Injury and Repair Systems)
Show Figures

Figure 1

Open AccessReview
DNA2—An Important Player in DNA Damage Response or Just Another DNA Maintenance Protein?
Int. J. Mol. Sci. 2017, 18(7), 1562; https://doi.org/10.3390/ijms18071562 - 18 Jul 2017
Cited by 7
Abstract
The human DNA2 (DNA replication helicase/nuclease 2) protein is expressed in both the nucleus and mitochondria, where it displays ATPase-dependent nuclease and helicase activities. DNA2 plays an important role in the removing of long flaps in DNA replication and long-patch base excision repair [...] Read more.
The human DNA2 (DNA replication helicase/nuclease 2) protein is expressed in both the nucleus and mitochondria, where it displays ATPase-dependent nuclease and helicase activities. DNA2 plays an important role in the removing of long flaps in DNA replication and long-patch base excision repair (LP-BER), interacting with the replication protein A (RPA) and the flap endonuclease 1 (FEN1). DNA2 can promote the restart of arrested replication fork along with Werner syndrome ATP-dependent helicase (WRN) and Bloom syndrome protein (BLM). In mitochondria, DNA2 can facilitate primer removal during strand-displacement replication. DNA2 is involved in DNA double strand (DSB) repair, in which it is complexed with BLM, RPA and MRN for DNA strand resection required for homologous recombination repair. DNA2 can be a major protein involved in the repair of complex DNA damage containing a DSB and a 5′ adduct resulting from a chemical group bound to DNA 5′ ends, created by ionizing radiation and several anticancer drugs, including etoposide, mitoxantrone and some anthracyclines. The role of DNA2 in telomere end maintenance and cell cycle regulation suggests its more general role in keeping genomic stability, which is impaired in cancer. Therefore DNA2 can be an attractive target in cancer therapy. This is supported by enhanced expression of DNA2 in many cancer cell lines with oncogene activation and premalignant cells. Therefore, DNA2 can be considered as a potential marker, useful in cancer therapy. DNA2, along with PARP1 inhibition, may be considered as a potential target for inducing synthetic lethality, a concept of killing tumor cells by targeting two essential genes. Full article
(This article belongs to the Special Issue DNA Injury and Repair Systems)
Show Figures

Graphical abstract

Back to TopTop