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Mechanisms and Regulation of Human DNA Replication
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Mechanisms and Regulation of Human DNA Replication

A special issue of Genes (ISSN 2073-4425). This special issue belongs to the section "Human Genomics and Genetic Diseases".

Deadline for manuscript submissions: closed (15 August 2024) | Viewed by 20040

Special Issue Editor

Prof. Dr. Heinz-Peter Nasheuer

E-Mail Website
Guest Editor
Centre for Chromosome Biology, School of Biological and Chemical Sciences, University of Galway, H91 TK33 Galway, Ireland
Interests: cell cycle control; DNA replication; genome stability; posttranslational modifications; replication fork proteins; initiation reaction; Okazaki fragment synthesis; protein‒protein and protein‒DNA interactions; enzyme mechanisms; DNA polymerases; DNA primase; ssDNA-binding proteins
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

In their influential review, ‘Hallmarks of Cancer: Next Generation’, Hanahan and Weinberg described the genome instability of cells as the most prominent enabling characteristic for cancer development, thus making it a central function on the long path for a normal cell becoming a cancer cell. The accurate and timely replication of the human genome is central for the prevention of genome instability and associated diseases including cancer and other genetic diseases. In recent years, substantial progress has been achieved in our understanding of the mechanisms and regulation of human DNA replication at all levels from cells to molecular structures.

This Special Issue, “Mechanisms and Regulation of Human DNA Replication”, aims to collect high-quality research articles, review articles, and communications in the field of human DNA replication from all areas of biomedical research including cell, molecular, and structural biology, which will advance our understanding of these essential cellular processes. These articles will display the current state of the art and may pave the way for future, novel medical therapies to prevent cancer and other genetic diseases.

Prof. Dr. Heinz-Peter Nasheuer
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 submissions that pass pre-check are 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. Genes is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). 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

  • cell cycle control
  • DNA replication
  • chromatin
  • post-translational modifications
  • initiation, elongation, and termination
  • replication forks
  • Okazaki fragments
  • centromeres and telomeres

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Published Papers (6 papers)

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Research

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26 pages, 12976 KiB  
Article
HROB Is Implicated in DNA Replication
by Julia Kutz, Hannes Schmietendorf, Sheikh Anika Rahman, Franz Opel and Helmut Pospiech
Genes 2024, 15(12), 1587; https://doi.org/10.3390/genes15121587 - 10 Dec 2024
Viewed by 1122
Abstract
DNA replication represents a series of precisely regulated events performed by a complex protein machinery that guarantees accurate duplication of the genetic information. Since DNA replication is permanently faced by a variety of exogenous and endogenous stressors, DNA damage response, repair and replication [...] Read more.
DNA replication represents a series of precisely regulated events performed by a complex protein machinery that guarantees accurate duplication of the genetic information. Since DNA replication is permanently faced by a variety of exogenous and endogenous stressors, DNA damage response, repair and replication must be closely coordinated to maintain genomic integrity. HROB has been identified recently as a binding partner and activator of the Mcm8/9 helicase involved in DNA interstrand crosslink (ICL) repair. We identified HROB independently as a nuclear protein whose expression is co-regulated with various DNA replication factors. Accordingly, the HROB protein level showed a maximum in S phase and a downregulation in quiescence. Structural prediction and homology searches revealed that HROB is a largely intrinsically disordered protein bearing a helix-rich region and a canonical oligonucleotide/oligosaccharide-binding-fold motif that originated early in eukaryotic evolution. Employing a flow cytometry Förster resonance energy transfer (FRET) assay, we detected associations between HROB and proteins of the DNA replication machinery. Moreover, ectopic expression of HROB protein led to an almost complete shutdown of DNA replication. The available data imply a function for HROB during DNA replication across barriers such as ICLs. Full article
(This article belongs to the Special Issue Mechanisms and Regulation of Human DNA Replication)
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26 pages, 9154 KiB  
Article
Developmental Changes in Genome Replication Progression in Pluripotent versus Differentiated Human Cells
by Sunil Kumar Pradhan, Teresa Lozoya, Paulina Prorok, Yue Yuan, Anne Lehmkuhl, Peng Zhang and M. Cristina Cardoso
Genes 2024, 15(3), 305; https://doi.org/10.3390/genes15030305 - 27 Feb 2024
Cited by 2 | Viewed by 2930
Abstract
DNA replication is a fundamental process ensuring the maintenance of the genome each time cells divide. This is particularly relevant early in development when cells divide profusely, later giving rise to entire organs. Here, we analyze and compare the genome replication progression in [...] Read more.
DNA replication is a fundamental process ensuring the maintenance of the genome each time cells divide. This is particularly relevant early in development when cells divide profusely, later giving rise to entire organs. Here, we analyze and compare the genome replication progression in human embryonic stem cells, induced pluripotent stem cells, and differentiated cells. Using single-cell microscopic approaches, we map the spatio-temporal genome replication as a function of chromatin marks/compaction level. Furthermore, we mapped the replication timing of subchromosomal tandem repeat regions and interspersed repeat sequence elements. Albeit the majority of these genomic repeats did not change their replication timing from pluripotent to differentiated cells, we found developmental changes in the replication timing of rDNA repeats. Comparing single-cell super-resolution microscopic data with data from genome-wide sequencing approaches showed comparable numbers of replicons and large overlap in origins numbers and genomic location among developmental states with a generally higher origin variability in pluripotent cells. Using ratiometric analysis of incorporated nucleotides normalized per replisome in single cells, we uncovered differences in fork speed throughout the S phase in pluripotent cells but not in somatic cells. Altogether, our data define similarities and differences on the replication program and characteristics in human cells at different developmental states. Full article
(This article belongs to the Special Issue Mechanisms and Regulation of Human DNA Replication)
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14 pages, 3525 KiB  
Article
Role of RPA Phosphorylation in the ATR-Dependent G2 Cell Cycle Checkpoint
by Shengqin Liu, Brendan M. Byrne, Thomas N. Byrne and Gregory G. Oakley
Genes 2023, 14(12), 2205; https://doi.org/10.3390/genes14122205 - 13 Dec 2023
Cited by 3 | Viewed by 2521
Abstract
Cells respond to DNA double-strand breaks by initiating DSB repair and ensuring a cell cycle checkpoint. The primary responder to DSB repair is non-homologous end joining, which is an error-prone repair pathway. However, when DSBs are generated after DNA replication in the G2 [...] Read more.
Cells respond to DNA double-strand breaks by initiating DSB repair and ensuring a cell cycle checkpoint. The primary responder to DSB repair is non-homologous end joining, which is an error-prone repair pathway. However, when DSBs are generated after DNA replication in the G2 phase of the cell cycle, a second DSB repair pathway, homologous recombination, can come into action. Both ATM and ATR are important for DSB-induced DSB repair and checkpoint responses. One method of ATM and ATR working together is through the DNA end resection of DSBs. As a readout and marker of DNA end resection, RPA is phosphorylated at Ser4/Ser8 of the N-terminus of RPA32 in response to DSBs. Here, the significance of RPA32 Ser4/Ser8 phosphorylation in response to DNA damage, specifically in the S phase to G2 phase of the cell cycle, is examined. RPA32 Ser4/Ser8 phosphorylation in G2 synchronized cells is necessary for increases in TopBP1 and Rad9 accumulation on chromatin and full activation of the ATR-dependent G2 checkpoint. In addition, our data suggest that RPA Ser4/Ser8 phosphorylation modulates ATM-dependent KAP-1 phosphorylation and Rad51 chromatin loading in G2 cells. Through the phosphorylation of RPA Ser4/Ser8, ATM acts as a partner with ATR in the G2 phase checkpoint response, regulating key downstream events including Rad9, TopBP1 phosphorylation and KAP-1 phosphorylation/activation via the targeting of RPA32 Ser4/Ser8. Full article
(This article belongs to the Special Issue Mechanisms and Regulation of Human DNA Replication)
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Review

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22 pages, 1537 KiB  
Review
Canonical and Non-Canonical Roles of Human DNA Polymerase η
by Salma Bedaiwi, Anam Usmani and Michael P. Carty
Genes 2024, 15(10), 1271; https://doi.org/10.3390/genes15101271 - 27 Sep 2024
Viewed by 1656
Abstract
DNA damage tolerance pathways that allow for the completion of replication following fork arrest are critical in maintaining genome stability during cell division. The main DNA damage tolerance pathways include strand switching, replication fork reversal and translesion synthesis (TLS). The TLS pathway is [...] Read more.
DNA damage tolerance pathways that allow for the completion of replication following fork arrest are critical in maintaining genome stability during cell division. The main DNA damage tolerance pathways include strand switching, replication fork reversal and translesion synthesis (TLS). The TLS pathway is mediated by specialised DNA polymerases that can accommodate altered DNA structures during DNA synthesis, and are important in allowing replication to proceed after fork arrest, preventing fork collapse that can generate more deleterious double-strand breaks in the genome. TLS may occur directly at the fork, or at gaps remaining behind the fork, in the process of post-replication repair. Inactivating mutations in the human POLH gene encoding the Y-family DNA polymerase Pol η causes the skin cancer-prone genetic disease xeroderma pigmentosum variant (XPV). Pol η also contributes to chemoresistance during cancer treatment by bypassing DNA lesions induced by anti-cancer drugs including cisplatin. We review the current understanding of the canonical role of Pol η in translesion synthesis following replication arrest, as well as a number of emerging non-canonical roles of the protein in other aspects of DNA metabolism. Full article
(This article belongs to the Special Issue Mechanisms and Regulation of Human DNA Replication)
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19 pages, 2429 KiB  
Review
Starting DNA Synthesis: Initiation Processes during the Replication of Chromosomal DNA in Humans
by Heinz Peter Nasheuer and Anna Marie Meaney
Genes 2024, 15(3), 360; https://doi.org/10.3390/genes15030360 - 14 Mar 2024
Cited by 2 | Viewed by 6601
Abstract
The initiation reactions of DNA synthesis are central processes during human chromosomal DNA replication. They are separated into two main processes: the initiation events at replication origins, the start of the leading strand synthesis for each replicon, and the numerous initiation events taking [...] Read more.
The initiation reactions of DNA synthesis are central processes during human chromosomal DNA replication. They are separated into two main processes: the initiation events at replication origins, the start of the leading strand synthesis for each replicon, and the numerous initiation events taking place during lagging strand DNA synthesis. In addition, a third mechanism is the re-initiation of DNA synthesis after replication fork stalling, which takes place when DNA lesions hinder the progression of DNA synthesis. The initiation of leading strand synthesis at replication origins is regulated at multiple levels, from the origin recognition to the assembly and activation of replicative helicase, the Cdc45–MCM2-7–GINS (CMG) complex. In addition, the multiple interactions of the CMG complex with the eukaryotic replicative DNA polymerases, DNA polymerase α-primase, DNA polymerase δ and ε, at replication forks play pivotal roles in the mechanism of the initiation reactions of leading and lagging strand DNA synthesis. These interactions are also important for the initiation of signalling at unperturbed and stalled replication forks, “replication stress” events, via ATR (ATM–Rad 3-related protein kinase). These processes are essential for the accurate transfer of the cells’ genetic information to their daughters. Thus, failures and dysfunctions in these processes give rise to genome instability causing genetic diseases, including cancer. In their influential review “Hallmarks of Cancer: New Dimensions”, Hanahan and Weinberg (2022) therefore call genome instability a fundamental function in the development process of cancer cells. In recent years, the understanding of the initiation processes and mechanisms of human DNA replication has made substantial progress at all levels, which will be discussed in the review. Full article
(This article belongs to the Special Issue Mechanisms and Regulation of Human DNA Replication)
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20 pages, 1638 KiB  
Review
The Intriguing Mystery of RPA Phosphorylation in DNA Double-Strand Break Repair
by Valerie J. Fousek-Schuller and Gloria E. O. Borgstahl
Genes 2024, 15(2), 167; https://doi.org/10.3390/genes15020167 - 27 Jan 2024
Cited by 2 | Viewed by 4113
Abstract
Human Replication Protein A (RPA) was historically discovered as one of the six components needed to reconstitute simian virus 40 DNA replication from purified components. RPA is now known to be involved in all DNA metabolism pathways that involve single-stranded DNA (ssDNA). Heterotrimeric [...] Read more.
Human Replication Protein A (RPA) was historically discovered as one of the six components needed to reconstitute simian virus 40 DNA replication from purified components. RPA is now known to be involved in all DNA metabolism pathways that involve single-stranded DNA (ssDNA). Heterotrimeric RPA comprises several domains connected by flexible linkers and is heavily regulated by post-translational modifications (PTMs). The structure of RPA has been challenging to obtain. Various structural methods have been applied, but a complete understanding of RPA’s flexible structure, its function, and how it is regulated by PTMs has yet to be obtained. This review will summarize recent literature concerning how RPA is phosphorylated in the cell cycle, the structural analysis of RPA, DNA and protein interactions involving RPA, and how PTMs regulate RPA activity and complex formation in double-strand break repair. There are many holes in our understanding of this research area. We will conclude with perspectives for future research on how RPA PTMs control double-strand break repair in the cell cycle. Full article
(This article belongs to the Special Issue Mechanisms and Regulation of Human DNA Replication)
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