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DNA Replication/Repair, and the DNA Damage Response in Human Disease
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DNA Replication/Repair, and the DNA Damage Response in Human Disease

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

Deadline for manuscript submissions: closed (10 October 2022) | Viewed by 26632

Special Issue Editors

Prof. Dr. Marietta Lee

E-Mail Website
Guest Editor
Department Biochemistry and Molecular Biology, New York Medical College, Valhalla, NY 10595, USA
Interests: DNA replication; DNA polymerases; DNA repair; cell cycle regulation
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Kristin A Eckert

E-Mail Website
Co-Guest Editor
Penn State College of Medicine, Department of Pathology, Hershey, PA, USA
Interests: DNA-directed DNA polymerase; DNA; microsatellite repeats; mutation; genome
Dr. Dong Zhang

E-Mail Website
Co-Guest Editor
Department of Biomedical Sciences, College of Osteopathic Medicine, New York Institute of Technology, Old Westbury, NY 11568, USA
Interests: DNA damage response; DNA repair; telomere biology and alternative lengthening of telomeres (ALT); ALT cancers
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Faithful duplication of the genome is vital for human fitness and health. The high-fidelity DNA polymerases for DNA replication, DNA damage response, and DNA repair all play essential roles in maintaining the stability of our genome. Mutations in genes involved in DNA replication, DNA damage response, and DNA repair can cause genome instability and affect the normal physiology of various cell types, tissues, and organs, leading to a variety of genetic diseases, including familial breast cancers, Fanconi anemia, and many others. In recent years, great advances have been achieved in understanding how DNA replication, DNA damage response, and DNA repair contribute to the clinical manifestations of various genetic diseases. Most importantly, tremendous strides have been made in developing precision medicine in treating these genetic diseases.

We welcome the submission of reviews, original research articles, and short communications that focus on identification, molecular mechanisms, and novel therapies in these genetic diseases.

Prof. Dr. Marietta Lee
Prof. Dr. Kristin A Eckert
Dr. Dong Zhang
Guest Editors

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

  • DNA replication
  • DNA repair
  • DNA damage response
  • genetic diseases
  • cancers

Published Papers (11 papers)

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Editorial

Jump to: Research, Review

3 pages, 186 KiB  
Editorial
Special Issue “DNA Replication/Repair, and the DNA Damage Response in Human Disease”
by Dong Zhang, Kristin A. Eckert and Marietta Y. W. T. Lee
Genes 2023, 14(4), 893; https://doi.org/10.3390/genes14040893 - 11 Apr 2023
Viewed by 1419
Abstract
Mutations of numerous genes involved in DNA replication, DNA repair, and DNA damage response (DDR) pathways lead to a variety of human diseases, including aging and cancer [...] Full article
(This article belongs to the Special Issue DNA Replication/Repair, and the DNA Damage Response in Human Disease)

Research

Jump to: Editorial, Review

18 pages, 2198 KiB  
Article
DNA Polymerase Delta Exhibits Altered Catalytic Properties on Lysine Acetylation
by Catherine Njeri, Sharon Pepenella, Tripthi Battapadi, Robert A. Bambara and Lata Balakrishnan
Genes 2023, 14(4), 774; https://doi.org/10.3390/genes14040774 - 23 Mar 2023
Cited by 1 | Viewed by 1431
Abstract
DNA polymerase delta is the primary polymerase that is involved in undamaged nuclear lagging strand DNA replication. Our mass-spectroscopic analysis has revealed that the human DNA polymerase δ is acetylated on subunits p125, p68, and p12. Using substrates that simulate Okazaki fragment intermediates, [...] Read more.
DNA polymerase delta is the primary polymerase that is involved in undamaged nuclear lagging strand DNA replication. Our mass-spectroscopic analysis has revealed that the human DNA polymerase δ is acetylated on subunits p125, p68, and p12. Using substrates that simulate Okazaki fragment intermediates, we studied alterations in the catalytic properties of acetylated polymerase and compared it to the unmodified form. The current data show that the acetylated form of human pol δ displays a higher polymerization activity compared to the unmodified form of the enzyme. Additionally, acetylation enhances the ability of the polymerase to resolve complex structures such as G-quadruplexes and other secondary structures that might be present on the template strand. More importantly, the ability of pol δ to displace a downstream DNA fragment is enhanced upon acetylation. Our current results suggest that acetylation has a profound effect on the activity of pol δ and supports the hypothesis that acetylation may promote higher-fidelity DNA replication. Full article
(This article belongs to the Special Issue DNA Replication/Repair, and the DNA Damage Response in Human Disease)
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26 pages, 10535 KiB  
Article
Suppressors of Break-Induced Replication in Human Cells
by Stanley Dean Rider, Jr., French J. Damewood IV, Rujuta Yashodhan Gadgil, David C. Hitch, Venicia Alhawach, Resha Shrestha, Matilyn Shanahan, Nathen Zavada and Michael Leffak
Genes 2023, 14(2), 398; https://doi.org/10.3390/genes14020398 - 03 Feb 2023
Cited by 1 | Viewed by 1823
Abstract
Short tandem DNA repeats are drivers of genome instability. To identify suppressors of break-induced mutagenesis human cells, unbiased genetic screens were conducted using a lentiviral shRNA library. The recipient cells possessed fragile non-B DNA that could induce DNA double-strand breaks (DSBs), integrated at [...] Read more.
Short tandem DNA repeats are drivers of genome instability. To identify suppressors of break-induced mutagenesis human cells, unbiased genetic screens were conducted using a lentiviral shRNA library. The recipient cells possessed fragile non-B DNA that could induce DNA double-strand breaks (DSBs), integrated at an ectopic chromosomal site adjacent to a thymidine kinase marker gene. Mutagenesis of the thymidine kinase gene rendered cells resistant to the nucleoside analog ganciclovir (GCV). The screen identified genes that have established roles in DNA replication and repair, chromatin modification, responses to ionizing radiation, and genes encoding proteins enriched at replication forks. Novel loci implicated in BIR included olfactory receptors, the G0S2 oncogene/tumor suppressor axis, the EIF3H-METTL3 translational regulator, and the SUDS3 subunit of the Sin3A corepressor. Consistent with a role in suppressing BIR, siRNA knockdown of selected candidates increased the frequency of the GCVr phenotype and increased DNA rearrangements near the ectopic non-B DNA. Inverse PCR and DNA sequence analyses showed that hits identified in the screen increased genome instability. Further analysis quantitated repeat-induced hypermutagenesis at the ectopic site and showed that knockdown of a primary hit, COPS2, induced mutagenic hotspots, remodeled the replication fork, and increased nonallelic chromosome template switches. Full article
(This article belongs to the Special Issue DNA Replication/Repair, and the DNA Damage Response in Human Disease)
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19 pages, 3872 KiB  
Article
Altered Nucleotide Insertion Mechanisms of Disease-Associated TERT Variants
by Griffin A. Welfer, Veniamin A. Borin, Luis M. Cortez, Patricia L. Opresko, Pratul K. Agarwal and Bret D. Freudenthal
Genes 2023, 14(2), 281; https://doi.org/10.3390/genes14020281 - 21 Jan 2023
Cited by 1 | Viewed by 1706
Abstract
Telomere biology disorders (TBDs) are a spectrum of diseases that arise from mutations in genes responsible for maintaining telomere integrity. Human telomerase reverse transcriptase (hTERT) adds nucleotides to chromosome ends and is frequently mutated in individuals with TBDs. Previous studies have provided insight [...] Read more.
Telomere biology disorders (TBDs) are a spectrum of diseases that arise from mutations in genes responsible for maintaining telomere integrity. Human telomerase reverse transcriptase (hTERT) adds nucleotides to chromosome ends and is frequently mutated in individuals with TBDs. Previous studies have provided insight into how relative changes in hTERT activity can lead to pathological outcomes. However, the underlying mechanisms describing how disease-associated variants alter the physicochemical steps of nucleotide insertion remain poorly understood. To address this, we applied single-turnover kinetics and computer simulations to the Tribolium castaneum TERT (tcTERT) model system and characterized the nucleotide insertion mechanisms of six disease-associated variants. Each variant had distinct consequences on tcTERT’s nucleotide insertion mechanism, including changes in nucleotide binding affinity, rates of catalysis, or ribonucleotide selectivity. Our computer simulations provide insight into how each variant disrupts active site organization, such as suboptimal positioning of active site residues, destabilization of the DNA 3′ terminus, or changes in nucleotide sugar pucker. Collectively, this work provides a holistic characterization of the nucleotide insertion mechanisms for multiple disease-associated TERT variants and identifies additional functions of key active site residues during nucleotide insertion. Full article
(This article belongs to the Special Issue DNA Replication/Repair, and the DNA Damage Response in Human Disease)
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16 pages, 5088 KiB  
Article
High Glucose Increases DNA Damage and Elevates the Expression of Multiple DDR Genes
by Mai A. Rahmoon, Reem A. Elghaish, Aya A. Ibrahim, Zina Alaswad, Mohamed Z. Gad, Sherif F. El-Khamisy and Menattallah Elserafy
Genes 2023, 14(1), 144; https://doi.org/10.3390/genes14010144 - 05 Jan 2023
Cited by 2 | Viewed by 2852
Abstract
The DNA Damage Response (DDR) pathways sense DNA damage and coordinate robust DNA repair and bypass mechanisms. A series of repair proteins are recruited depending on the type of breaks and lesions to ensure overall survival. An increase in glucose levels was shown [...] Read more.
The DNA Damage Response (DDR) pathways sense DNA damage and coordinate robust DNA repair and bypass mechanisms. A series of repair proteins are recruited depending on the type of breaks and lesions to ensure overall survival. An increase in glucose levels was shown to induce genome instability, yet the links between DDR and glucose are still not well investigated. In this study, we aimed to identify dysregulation in the transcriptome of normal and cancerous breast cell lines upon changing glucose levels. We first performed bioinformatics analysis using a microarray dataset containing the triple-negative breast cancer (TNBC) MDA-MB-231 and the normal human mammary epithelium MCF10A cell lines grown in high glucose (HG) or in the presence of the glycolysis inhibitor 2-deoxyglucose (2DG). Interestingly, multiple DDR genes were significantly upregulated in both cell lines grown in HG. In the wet lab, we remarkably found that HG results in severe DNA damage to TNBC cells as observed using the comet assay. In addition, several DDR genes were confirmed to be upregulated using qPCR analysis in the same cell line. Our results propose a strong need for DDR pathways in the presence of HG to oppose the severe DNA damage induced in cells. Full article
(This article belongs to the Special Issue DNA Replication/Repair, and the DNA Damage Response in Human Disease)
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18 pages, 4422 KiB  
Article
Flap Endonuclease 1 Endonucleolytically Processes RNA to Resolve R-Loops through DNA Base Excision Repair
by Eduardo E. Laverde, Aris A. Polyzos, Pawlos P. Tsegay, Mohammad Shaver, Joshua D. Hutcheson, Lata Balakrishnan, Cynthia T. McMurray and Yuan Liu
Genes 2023, 14(1), 98; https://doi.org/10.3390/genes14010098 - 29 Dec 2022
Cited by 4 | Viewed by 2417
Abstract
Flap endonuclease 1 (FEN1) is an essential enzyme that removes RNA primers and base lesions during DNA lagging strand maturation and long-patch base excision repair (BER). It plays a crucial role in maintaining genome stability and integrity. FEN1 is also implicated in RNA [...] Read more.
Flap endonuclease 1 (FEN1) is an essential enzyme that removes RNA primers and base lesions during DNA lagging strand maturation and long-patch base excision repair (BER). It plays a crucial role in maintaining genome stability and integrity. FEN1 is also implicated in RNA processing and biogenesis. A recent study from our group has shown that FEN1 is involved in trinucleotide repeat deletion by processing the RNA strand in R-loops through BER, further suggesting that the enzyme can modulate genome stability by facilitating the resolution of R-loops. However, it remains unknown how FEN1 can process RNA to resolve an R-loop. In this study, we examined the FEN1 cleavage activity on the RNA:DNA hybrid intermediates generated during DNA lagging strand processing and BER in R-loops. We found that both human and yeast FEN1 efficiently cleaved an RNA flap in the intermediates using its endonuclease activity. We further demonstrated that FEN1 was recruited to R-loops in normal human fibroblasts and senataxin-deficient (AOA2) fibroblasts, and its R-loop recruitment was significantly increased by oxidative DNA damage. We showed that FEN1 specifically employed its endonucleolytic cleavage activity to remove the RNA strand in an R-loop during BER. We found that FEN1 coordinated its DNA and RNA endonucleolytic cleavage activity with the 3′-5′ exonuclease of APE1 to resolve the R-loop. Our results further suggest that FEN1 employed its unique tracking mechanism to endonucleolytically cleave the RNA strand in an R-loop by coordinating with other BER enzymes and cofactors during BER. Our study provides the first evidence that FEN1 endonucleolytic cleavage can result in the resolution of R-loops via the BER pathway, thereby maintaining genome integrity. Full article
(This article belongs to the Special Issue DNA Replication/Repair, and the DNA Damage Response in Human Disease)
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Review

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24 pages, 1183 KiB  
Review
The Molecular and Cellular Basis of Hutchinson–Gilford Progeria Syndrome and Potential Treatments
by Noelle J. Batista, Sanket G. Desai, Alexis M. Perez, Alexa Finkelstein, Rachel Radigan, Manrose Singh, Aaron Landman, Brian Drittel, Daniella Abramov, Mina Ahsan, Samantha Cornwell and Dong Zhang
Genes 2023, 14(3), 602; https://doi.org/10.3390/genes14030602 - 27 Feb 2023
Cited by 7 | Viewed by 4384
Abstract
Hutchinson–Gilford progeria syndrome (HGPS) is a rare, autosomal-dominant, and fatal premature aging syndrome. HGPS is most often derived from a de novo point mutation in the LMNA gene, which results in an alternative splicing defect and the generation of the mutant protein, progerin. [...] Read more.
Hutchinson–Gilford progeria syndrome (HGPS) is a rare, autosomal-dominant, and fatal premature aging syndrome. HGPS is most often derived from a de novo point mutation in the LMNA gene, which results in an alternative splicing defect and the generation of the mutant protein, progerin. Progerin behaves in a dominant-negative fashion, leading to a variety of cellular and molecular changes, including nuclear abnormalities, defective DNA damage response (DDR) and DNA repair, and accelerated telomere attrition. Intriguingly, many of the manifestations of the HGPS cells are shared with normal aging cells. However, at a clinical level, HGPS does not fully match normal aging because of the accelerated nature of the phenotypes and its primary effects on connective tissues. Furthermore, the epigenetic changes in HGPS patients are of great interest and may play a crucial role in the pathogenesis of HGPS. Finally, various treatments for the HGPS patients have been developed in recent years with important effects at a cellular level, which translate to symptomatic improvement and increased lifespan. Full article
(This article belongs to the Special Issue DNA Replication/Repair, and the DNA Damage Response in Human Disease)
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17 pages, 1254 KiB  
Review
Telomere Fragility and MiDAS: Managing the Gaps at the End of the Road
by Ryan P. Barnes, Sanjana A. Thosar and Patricia L. Opresko
Genes 2023, 14(2), 348; https://doi.org/10.3390/genes14020348 - 29 Jan 2023
Cited by 2 | Viewed by 3133
Abstract
Telomeres present inherent difficulties to the DNA replication machinery due to their repetitive sequence content, formation of non-B DNA secondary structures, and the presence of the nucleo-protein t-loop. Especially in cancer cells, telomeres are hot spots for replication stress, which can result in [...] Read more.
Telomeres present inherent difficulties to the DNA replication machinery due to their repetitive sequence content, formation of non-B DNA secondary structures, and the presence of the nucleo-protein t-loop. Especially in cancer cells, telomeres are hot spots for replication stress, which can result in a visible phenotype in metaphase cells termed “telomere fragility”. A mechanism cells employ to mitigate replication stress, including at telomeres, is DNA synthesis in mitosis (MiDAS). While these phenomena are both observed in mitotic cells, the relationship between them is poorly understood; however, a common link is DNA replication stress. In this review, we will summarize what is known to regulate telomere fragility and telomere MiDAS, paying special attention to the proteins which play a role in these telomere phenotypes. Full article
(This article belongs to the Special Issue DNA Replication/Repair, and the DNA Damage Response in Human Disease)
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12 pages, 277 KiB  
Review
Nontraditional Roles of DNA Polymerase Eta Support Genome Duplication and Stability
by Kristin A. Eckert
Genes 2023, 14(1), 175; https://doi.org/10.3390/genes14010175 - 09 Jan 2023
Cited by 2 | Viewed by 2098
Abstract
DNA polymerase eta (Pol η) is a Y-family polymerase and the product of the POLH gene. Autosomal recessive inheritance of POLH mutations is the cause of the xeroderma pigmentosum variant, a cancer predisposition syndrome. This review summarizes mounting evidence for expanded Pol η [...] Read more.
DNA polymerase eta (Pol η) is a Y-family polymerase and the product of the POLH gene. Autosomal recessive inheritance of POLH mutations is the cause of the xeroderma pigmentosum variant, a cancer predisposition syndrome. This review summarizes mounting evidence for expanded Pol η cellular functions in addition to DNA lesion bypass that are critical for maintaining genome stability. In vitro, Pol η displays efficient DNA synthesis through difficult-to-replicate sequences, catalyzes D-loop extensions, and utilizes RNA–DNA hybrid templates. Human Pol η is constitutively present at the replication fork. In response to replication stress, Pol η is upregulated at the transcriptional and protein levels, and post-translational modifications regulate its localization to chromatin. Numerous studies show that Pol η is required for efficient common fragile site replication and stability. Additionally, Pol η can be recruited to stalled replication forks through protein–protein interactions, suggesting a broader role in replication fork recovery. During somatic hypermutations, Pol η is recruited by mismatch repair proteins and is essential for VH gene A:T basepair mutagenesis. Within the global context of repeat-dense genomes, the recruitment of Pol η to perform specialized functions during replication could promote genome stability by interrupting pure repeat arrays with base substitutions. Alternatively, not engaging Pol η in genome duplication is costly, as the absence of Pol η leads to incomplete replication and increased chromosomal instability. Full article
(This article belongs to the Special Issue DNA Replication/Repair, and the DNA Damage Response in Human Disease)
23 pages, 2405 KiB  
Review
The Role of PARP1 and PAR in ATP-Independent Nucleosome Reorganisation during the DNA Damage Response
by Ekaterina A. Belousova and Olga I. Lavrik
Genes 2023, 14(1), 112; https://doi.org/10.3390/genes14010112 - 30 Dec 2022
Cited by 5 | Viewed by 2161
Abstract
The functioning of the eukaryotic cell genome is mediated by sophisticated protein-nucleic-acid complexes, whose minimal structural unit is the nucleosome. After the damage to genomic DNA, repair proteins need to gain access directly to the lesion; therefore, the initiation of the DNA damage [...] Read more.
The functioning of the eukaryotic cell genome is mediated by sophisticated protein-nucleic-acid complexes, whose minimal structural unit is the nucleosome. After the damage to genomic DNA, repair proteins need to gain access directly to the lesion; therefore, the initiation of the DNA damage response inevitably leads to local chromatin reorganisation. This review focuses on the possible involvement of PARP1, as well as proteins acting nucleosome compaction, linker histone H1 and non-histone chromatin protein HMGB1. The polymer of ADP-ribose is considered the main regulator during the development of the DNA damage response and in the course of assembly of the correct repair complex. Full article
(This article belongs to the Special Issue DNA Replication/Repair, and the DNA Damage Response in Human Disease)
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10 pages, 1987 KiB  
Review
POLDIP3: At the Crossroad of RNA and DNA Metabolism
by Manrose Singh, Sufang Zhang, Alexis M. Perez, Ernest Y. C. Lee, Marietta Y. W. T. Lee and Dong Zhang
Genes 2022, 13(11), 1921; https://doi.org/10.3390/genes13111921 - 22 Oct 2022
Cited by 2 | Viewed by 1679
Abstract
POLDIP3 was initially identified as a DNA polymerase delta (Pol δ) interacting protein almost twenty years ago. Intriguingly, it also interacts with proteins involved in a variety of RNA related biological processes, such as transcription, pre-mRNA splicing, mRNA export, and translation. Studies in [...] Read more.
POLDIP3 was initially identified as a DNA polymerase delta (Pol δ) interacting protein almost twenty years ago. Intriguingly, it also interacts with proteins involved in a variety of RNA related biological processes, such as transcription, pre-mRNA splicing, mRNA export, and translation. Studies in recent years revealed that POLDIP3 also plays critical roles in disassembling genome wide R-loop formation and activating the DNA damage checkpoint in vivo. Here, we review the functions of POLDIP3 in various RNA and DNA related cellular processes. We then propose a unified model to illustrate how POLDIP3 plays such a versatile role at the crossroad of the RNA and DNA metabolism. Full article
(This article belongs to the Special Issue DNA Replication/Repair, and the DNA Damage Response in Human Disease)
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