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Mechanisms of DNA Damage, Repair and Mutagenesis
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Mechanisms of DNA Damage, Repair and Mutagenesis

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

Deadline for manuscript submissions: closed (5 November 2021) | Viewed by 54758

Special Issue Editors

Prof. Dr. Martin Kupiec

E-Mail Website
Guest Editor
The Shmunis School of Biomedicine & Cancer Research, Tel Aviv University, Ramat Aviv, Tel Aviv 69978, Israel
Interests: Saccharomyces cerevisiae; Schizosaccharomyces pombe; yeast; genome stability; DNA repair; telomeres
Special Issues, Collections and Topics in MDPI journals
Dr. Maciej Wnuk

E-Mail Website
Guest Editor
Department of Biotechnology, University of Rzeszow, Pigonia 1 A0, 35-310 Rzeszow, Poland
Interests: cancer cells; yeast cell biology; chromosomes; genomic instability; senescence; toxicology
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues, 

It is well known that DNA damage may affect the development and differentiation process in all living organisms leading to death, increased cellular heterogeneity, premature senescence, or uncontrolled, abnormal growth of cells. The stability of the genome is strictly related to the activity of mechanisms able to detect and repair DNA breaks, damaged or incompletely replicated DNA or DNA sequence mismatches and mutation. In this Special Issue of Genes, we welcome reviews, new methods, original research articles, and communications that advance our understanding of all aspects of mechanisms of DNA damage, repair, and mutagenesis from evolutionary aspects to biological, medical, and biotechnological implications. While the mechanisms involved in the maintenance of telomere, rDNA, centromere, and heterochromatin will be of special interest, we are open to any advancement exploring the genome structural variation, chromosomal aberrations, including aneuploidy as well as molecular epidemiology and mechanisms of genotoxicity.

Prof. Dr. Martin Kupiec
Dr. Maciej Wnuk
Guest Editors

Manuscript Submission Information

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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 damage
  • DNA repair
  • Mutagenesis
  • Genomic instability
  • Chromosome maintenance
  • DNA replication
  • DNA damage checkpoint

Published Papers (16 papers)

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Research

Jump to: Review

16 pages, 4248 KiB  
Article
Time Course Analysis of Genome-Wide Identification of Mutations Induced by and Genes Expressed in Response to Carbon Ion Beam Irradiation in Rice (Oryza sativa L.)
by Jian Zhang, Ziai Peng, Qiling Liu, Guili Yang, Libin Zhou, Wenjian Li, Hui Wang, Zhiqiang Chen and Tao Guo
Genes 2021, 12(9), 1391; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12091391 - 09 Sep 2021
Cited by 4 | Viewed by 1931
Abstract
Heavy-ion irradiation is a powerful mutagen and is widely used for mutation breeding. In this study, using whole-genome sequencing (WGS) and RNA sequencing (RNA-seq) techniques, we comprehensively characterized these dynamic changes caused by mutations at three time points (48, 96, and 144 h [...] Read more.
Heavy-ion irradiation is a powerful mutagen and is widely used for mutation breeding. In this study, using whole-genome sequencing (WGS) and RNA sequencing (RNA-seq) techniques, we comprehensively characterized these dynamic changes caused by mutations at three time points (48, 96, and 144 h after irradiation) and the expression profiles of rice seeds irradiated with C ions at two doses. Subsequent WGS analysis revealed that more mutations were detected in response to 40 Gy carbon ion beam (CIB) irradiation than 80 Gy of CIB irradiation at the initial stage (48 h post-irradiation). In the mutants generated from both irradiation doses, single-base substitutions (SBSs) were the most frequent type of mutation induced by CIB irradiation. Among the mutations, the predominant ones were C:T and A:G transitions. CIB irradiation also induced many short InDel mutations. RNA-seq analysis at the three time points showed that the number of differentially expressed genes (DEGs) was highest at 48 h post-irradiation. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis of the DEGs showed that the “replication and repair” pathway was enriched specifically 48 h post-irradiation. These results indicate that the DNA damage response (DDR) and the mechanism of DNA repair tend to quickly start within the initial stage (48 h) after irradiation. Full article
(This article belongs to the Special Issue Mechanisms of DNA Damage, Repair and Mutagenesis)
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16 pages, 3452 KiB  
Article
miR-27b-3p a Negative Regulator of DSB-DNA Repair
by Ricardo I. Peraza-Vega, Mahara Valverde and Emilio Rojas
Genes 2021, 12(9), 1333; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12091333 - 27 Aug 2021
Cited by 3 | Viewed by 1944
Abstract
Understanding the regulation of DNA repair mechanisms is of utmost importance to identify altered cellular processes that lead to diseases such as cancer through genomic instability. In this sense, miRNAs have shown a crucial role. Specifically, miR-27b-3 biogenesis has been shown to be [...] Read more.
Understanding the regulation of DNA repair mechanisms is of utmost importance to identify altered cellular processes that lead to diseases such as cancer through genomic instability. In this sense, miRNAs have shown a crucial role. Specifically, miR-27b-3 biogenesis has been shown to be induced in response to DNA damage, suggesting that this microRNA has a role in DNA repair. In this work, we show that the overexpression of miR-27b-3p reduces the ability of cells to repair DNA lesions, mainly double-stranded breaks (DSB), and causes the deregulation of genes involved in homologous recombination repair (HRR), base excision repair (BER), and the cell cycle. DNA damage was induced in BALB/c-3T3 cells, which overexpress miR-27b-3p, using xenobiotic agents with specific mechanisms of action that challenge different repair mechanisms to determine their reparative capacity. In addition, we evaluated the expression of 84 DNA damage signaling and repair genes and performed pathway enrichment analysis to identify altered cellular processes. Taken together, our results indicate that miR-27b-3p acts as a negative regulator of DNA repair when overexpressed. Full article
(This article belongs to the Special Issue Mechanisms of DNA Damage, Repair and Mutagenesis)
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17 pages, 2758 KiB  
Article
Genetic Analysis of the Hsm3 Protein Function in Yeast Saccharomyces cerevisiae NuB4 Complex
by Tatiyana A. Evstyukhina, Elena A. Alekseeva, Dmitriy V. Fedorov, Vyacheslav T. Peshekhonov and Vladimir G. Korolev
Genes 2021, 12(7), 1083; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12071083 - 17 Jul 2021
Cited by 2 | Viewed by 1907
Abstract
In the nuclear compartment of yeast, NuB4 core complex consists of three proteins, Hat1, Hat2, and Hif1, and interacts with a number of other factors. In particular, it was shown that NuB4 complex physically interacts with Hsm3p. Early we demonstrated that the gene [...] Read more.
In the nuclear compartment of yeast, NuB4 core complex consists of three proteins, Hat1, Hat2, and Hif1, and interacts with a number of other factors. In particular, it was shown that NuB4 complex physically interacts with Hsm3p. Early we demonstrated that the gene HSM3 participates in the control of replicative and reparative spontaneous mutagenesis, and that hsm3Δ mutants increase the frequency of mutations induced by different mutagens. It was previously believed that the HSM3 gene controlled only some minor repair processes in the cell, but later it was suggested that it had a chaperone function with its participation in proteasome assembly. In this work, we analyzed the properties of three hsm3Δ, hif1Δ, and hat1Δ mutants. The results obtained showed that the Hsm3 protein may be a functional subunit of NuB4 complex. It has been shown that hsm3- and hif1-dependent UV-induced mutagenesis is completely suppressed by inactivation of the Polη polymerase. We showed a significant role of Polη for hsm3-dependent mutagenesis at non-bipyrimidine sites (NBP sites). The efficiency of expression of RNR (RiboNucleotid Reducase) genes after UV irradiation in hsm3Δ and hif1Δ mutants was several times lower than in wild-type cells. Thus, we have presented evidence that significant increase in the dNTP levels suppress hsm3- and hif1-dependent mutagenesis and Polη is responsible for hsm3- and hif1-dependent mutagenesis. Full article
(This article belongs to the Special Issue Mechanisms of DNA Damage, Repair and Mutagenesis)
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9 pages, 1746 KiB  
Communication
Mapping and Analysis of Swi5 and Sfr1 Phosphorylation Sites
by Andrea Sevcovicova, Jana Plava, Matej Gazdarica, Eva Szabova, Barbora Huraiova, Katarina Gaplovska-Kysela, Ingrid Cipakova, Lubos Cipak and Juraj Gregan
Genes 2021, 12(7), 1014; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12071014 - 30 Jun 2021
Cited by 1 | Viewed by 2188
Abstract
The evolutionarily conserved Swi5-Sfr1 complex plays an important role in homologous recombination, a process crucial for the maintenance of genomic integrity. Here, we purified Schizosaccharomyces pombe Swi5-Sfr1 complex from meiotic cells and analyzed it by mass spectrometry. Our analysis revealed new phosphorylation sites [...] Read more.
The evolutionarily conserved Swi5-Sfr1 complex plays an important role in homologous recombination, a process crucial for the maintenance of genomic integrity. Here, we purified Schizosaccharomyces pombe Swi5-Sfr1 complex from meiotic cells and analyzed it by mass spectrometry. Our analysis revealed new phosphorylation sites on Swi5 and Sfr1. We found that mutations that prevent phosphorylation of Swi5 and Sfr1 do not impair their function but swi5 and sfr1 mutants encoding phosphomimetic aspartate at the identified phosphorylation sites are only partially functional. We conclude that during meiosis, Swi5 associates with Sfr1 and both Swi5 and Sfr1 proteins are phosphorylated. However, the functional relevance of Swi5 and Sfr1 phosphorylation remains to be determined. Full article
(This article belongs to the Special Issue Mechanisms of DNA Damage, Repair and Mutagenesis)
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15 pages, 20440 KiB  
Article
Kinase Inhibitors of DNA-PK, ATM and ATR in Combination with Ionizing Radiation Can Increase Tumor Cell Death in HNSCC Cells While Sparing Normal Tissue Cells
by Eva-Maria Faulhaber, Tina Jost, Julia Symank, Julian Scheper, Felix Bürkel, Rainer Fietkau, Markus Hecht and Luitpold V. Distel
Genes 2021, 12(6), 925; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12060925 - 17 Jun 2021
Cited by 18 | Viewed by 3333
Abstract
(1) Kinase inhibitors (KI) targeting components of the DNA damage repair pathway are a promising new type of drug. Combining them with ionizing radiation therapy (IR), which is commonly used for treatment of head and neck tumors, could improve tumor control, but could [...] Read more.
(1) Kinase inhibitors (KI) targeting components of the DNA damage repair pathway are a promising new type of drug. Combining them with ionizing radiation therapy (IR), which is commonly used for treatment of head and neck tumors, could improve tumor control, but could also increase negative side effects on surrounding normal tissue. (2) The effect of KI of the DDR (ATMi: AZD0156; ATRi: VE-822, dual DNA-PKi/mTORi: CC-115) in combination with IR on HPV-positive and HPV-negative HNSCC and healthy skin cells was analyzed. Cell death and cell cycle arrest were determined using flow cytometry. Additionally, clonogenic survival and migration were analyzed. (3) Studied HNSCC cell lines reacted differently to DDRi. An increase in cell death for all of the malignant cells could be observed when combining IR and KI. Healthy fibroblasts were not affected by simultaneous treatment. Migration was partially impaired. Influence on the cell cycle varied between the cell lines and inhibitors; (4) In conclusion, a combination of DDRi with IR could be feasible for patients with HNSCC. Side effects on healthy cells are expected to be limited to normal radiation-induced response. Formation of metastases could be decreased because cell migration is impaired partially. The treatment outcome for HPV-negative tumors tends to be improved by combined treatment. Full article
(This article belongs to the Special Issue Mechanisms of DNA Damage, Repair and Mutagenesis)
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24 pages, 7561 KiB  
Article
Rice (Oryza sativa) TIR1 and 5′adamantyl-IAA Significantly Improve the Auxin-Inducible Degron System in Schizosaccharomyces pombe
by Adam T. Watson, Storm Hassell-Hart, John Spencer and Antony M. Carr
Genes 2021, 12(6), 882; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12060882 - 08 Jun 2021
Cited by 8 | Viewed by 4189
Abstract
The auxin-inducible degron (AID) system is a powerful tool to induce targeted degradation of proteins in eukaryotic model organisms. The efficiency of the existing Schizosaccharomyces pombe AID system is limited due to the fusion of the F-box protein TIR1 protein to the SCF [...] Read more.
The auxin-inducible degron (AID) system is a powerful tool to induce targeted degradation of proteins in eukaryotic model organisms. The efficiency of the existing Schizosaccharomyces pombe AID system is limited due to the fusion of the F-box protein TIR1 protein to the SCF component, Skp1 (Skp1-TIR1). Here, we report an improved AID system for S. pombe that uses the TIR1 from Oryza sativa (OsTIR1) not fused to Skp1. Furthermore, we demonstrate that degradation efficiency can be improved by pairing an OsTIR1 auxin-binding site mutant, OsTIR1F74A, with an auxin analogue, 5′adamantyl-IAA (AID2). We provide evidence for the enhanced functionality of the OsTIR1 AID and AID2 systems by application to the essential DNA replication factor Mcm4 and to a non-essential recombination protein, Rad52. Unlike AID, no detectable auxin-independent depletion of AID-tagged proteins was observed using AID2. Full article
(This article belongs to the Special Issue Mechanisms of DNA Damage, Repair and Mutagenesis)
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13 pages, 1819 KiB  
Article
PARP Inhibitors Talazoparib and Niraparib Sensitize Melanoma Cells to Ionizing Radiation
by Stephanie Jonuscheit, Tina Jost, Fritzi Gajdošová, Maximilian Wrobel, Markus Hecht, Rainer Fietkau and Luitpold Distel
Genes 2021, 12(6), 849; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12060849 - 31 May 2021
Cited by 12 | Viewed by 3359
Abstract
(1) Background: Niraparib and Talazoparib are poly (ADP-ribose) polymerase (PARP) 1/2 inhibitors. It is assumed that combining PARP inhibitors with radiotherapy could be beneficial for cancer treatment. In this study, melanoma cells were treated with Niraparib and Talazoparib in combination with ionizing radiation [...] Read more.
(1) Background: Niraparib and Talazoparib are poly (ADP-ribose) polymerase (PARP) 1/2 inhibitors. It is assumed that combining PARP inhibitors with radiotherapy could be beneficial for cancer treatment. In this study, melanoma cells were treated with Niraparib and Talazoparib in combination with ionizing radiation (IR). (2) Methods: The effects of Talazoparib and Niraparib in combination with IR on cell death, clonogenicity and cell cycle arrest were studied in healthy primary fibroblasts and primary melanoma cells. (3) Results: The melanoma cells had a higher PARP1 and PARP2 content than the healthy fibroblasts, and further increased their PARP2 content after the combination therapy. PARP inhibitors both sensitized fibroblasts and melanoma cells to IR. A clear supra-additive effect of KI+IR treatment was detected in two melanoma cell lines analyzing the surviving fraction. The cell death rate increased in the healthy fibroblasts, but to a larger extent in melanoma cells after combined treatment. Finally, a lower percentage of cells in the radiosensitive G2/M phase is present in the healthy fibroblasts compared to the melanoma cells. (4) Conclusions: Both PARP inhibitors sensitize melanoma cells to IR. Healthy tissue seems to be less affected than melanoma cells. However, the great heterogeneity of the results suggests prior testing of the tumor cells in order to personalize the treatment. Full article
(This article belongs to the Special Issue Mechanisms of DNA Damage, Repair and Mutagenesis)
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14 pages, 1109 KiB  
Article
The Genotoxic and Pro-Apoptotic Activities of Advanced Glycation End-Products (MAGE) Measured with Micronuclei Assay Are Inhibited by Their Low Molecular Mass Counterparts
by Monika Czech, Maria Konopacka, Jacek Rogoliński, Zbigniew Maniakowski, Magdalena Staniszewska, Łukasz Łaczmański, Danuta Witkowska and Andrzej Gamian
Genes 2021, 12(5), 729; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12050729 - 13 May 2021
Cited by 5 | Viewed by 1916
Abstract
An association between the cancer invasive activities of cells and their exposure to advanced glycation end-products (AGEs) was described early in some reports. An incubation of cells with BSA–AGE (bovine serum albumin–AGE), BSA–carboxymethyllysine and BSA–methylglyoxal (BSA–MG) resulted in a significant increase in DNA [...] Read more.
An association between the cancer invasive activities of cells and their exposure to advanced glycation end-products (AGEs) was described early in some reports. An incubation of cells with BSA–AGE (bovine serum albumin–AGE), BSA–carboxymethyllysine and BSA–methylglyoxal (BSA–MG) resulted in a significant increase in DNA damage. We examined the genotoxic activity of new products synthesized under nonaqueous conditions. These were high molecular mass MAGEs (HMW–MAGEs) formed from protein and melibiose and low molecular mass MAGEs (LMW–MAGEs) obtained from the melibiose and N-α-acetyllysine and N-α-acetylarginine. We have observed by measuring of micronuclei in human lymphocytes in vitro that the studied HMW–MAGEs expressed the genotoxicity. The number of micronuclei (MN) in lymphocytes reached 40.22 ± 5.34 promille (MN/1000CBL), compared to 28.80 ± 6.50 MN/1000 CBL for the reference BSA–MG, whereas a control value was 20.66 ± 1.39 MN/1000CBL. However, the LMW–MAGE fractions did not induce micronuclei formation in the culture of lymphocytes and partially protected DNA against damage in the cells irradiated with X-ray. Human melanoma and all other studied cells, such as bronchial epithelial cells, lung cancer cells and colorectal cancer cells, are susceptible to the genotoxic effects of HMW–MAGEs. The LMW–MAGEs are not genotoxic, while they inhibit HMW–MAGE genotoxic activity. With regard to apoptosis, it is induced with the HMW–MAGE compounds, in the p53 independent way, whereas the low molecular mass product inhibits the apoptosis induction. Further investigations will potentially indicate beneficial apoptotic effect on cancer cells. Full article
(This article belongs to the Special Issue Mechanisms of DNA Damage, Repair and Mutagenesis)
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Review

Jump to: Research

12 pages, 1961 KiB  
Review
Mechanisms of DNA Mobilization and Sequestration
by Kerry Bloom and Daniel Kolbin
Genes 2022, 13(2), 352; https://0-doi-org.brum.beds.ac.uk/10.3390/genes13020352 - 16 Feb 2022
Cited by 1 | Viewed by 2360
Abstract
The entire genome becomes mobilized following DNA damage. Understanding the mechanisms that act at the genome level requires that we embrace experimental and computational strategies to capture the behavior of the long-chain DNA polymer, which is the building block for the chromosome. Long-chain [...] Read more.
The entire genome becomes mobilized following DNA damage. Understanding the mechanisms that act at the genome level requires that we embrace experimental and computational strategies to capture the behavior of the long-chain DNA polymer, which is the building block for the chromosome. Long-chain polymers exhibit constrained, sub-diffusive motion in the nucleus. Cross-linking proteins, including cohesin and condensin, have a disproportionate effect on genome organization in their ability to stabilize transient interactions. Cross-linking proteins can segregate the genome into sub-domains through polymer–polymer phase separation (PPPS) and can drive the formation of gene clusters through small changes in their binding kinetics. Principles from polymer physics provide a means to unravel the mysteries hidden in the chains of life. Full article
(This article belongs to the Special Issue Mechanisms of DNA Damage, Repair and Mutagenesis)
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16 pages, 1939 KiB  
Review
3D Genome Organization: Causes and Consequences for DNA Damage and Repair
by Ànnia Carré-Simon and Emmanuelle Fabre
Genes 2022, 13(1), 7; https://0-doi-org.brum.beds.ac.uk/10.3390/genes13010007 - 21 Dec 2021
Cited by 8 | Viewed by 4043
Abstract
The inability to repair damaged DNA severely compromises the integrity of any organism. In eukaryotes, the DNA damage response (DDR) operates within chromatin, a tightly organized DNA–histone complex in a non-random manner within the nucleus. Chromatin thus orchestrates various cellular processes, including repair. [...] Read more.
The inability to repair damaged DNA severely compromises the integrity of any organism. In eukaryotes, the DNA damage response (DDR) operates within chromatin, a tightly organized DNA–histone complex in a non-random manner within the nucleus. Chromatin thus orchestrates various cellular processes, including repair. Here, we examine the chromatin landscape before, during, and after the DNA damage, focusing on double strand breaks (DSBs). We study how chromatin is modified during the repair process, not only around the damaged region (in cis), but also genome-wide (in trans). Recent evidence has highlighted a complex landscape in which different chromatin parameters (stiffness, compaction, loops) are transiently modified, defining “codes” for each specific stage of the DDR. We illustrate a novel aspect of DDR where chromatin modifications contribute to the movement of DSB-damaged chromatin, as well as undamaged chromatin, ensuring the mobilization of DSBs, their clustering, and their repair processes. Full article
(This article belongs to the Special Issue Mechanisms of DNA Damage, Repair and Mutagenesis)
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18 pages, 1621 KiB  
Review
Role and Regulation of the RECQL4 Family during Genomic Integrity Maintenance
by Thong T. Luong and Kara A. Bernstein
Genes 2021, 12(12), 1919; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12121919 - 29 Nov 2021
Cited by 9 | Viewed by 3223
Abstract
RECQL4 is a member of the evolutionarily conserved RecQ family of 3’ to 5’ DNA helicases. RECQL4 is critical for maintaining genomic stability through its functions in DNA repair, recombination, and replication. Unlike many DNA repair proteins, RECQL4 has unique functions in many [...] Read more.
RECQL4 is a member of the evolutionarily conserved RecQ family of 3’ to 5’ DNA helicases. RECQL4 is critical for maintaining genomic stability through its functions in DNA repair, recombination, and replication. Unlike many DNA repair proteins, RECQL4 has unique functions in many of the central DNA repair pathways such as replication, telomere, double-strand break repair, base excision repair, mitochondrial maintenance, nucleotide excision repair, and crosslink repair. Consistent with these diverse roles, mutations in RECQL4 are associated with three distinct genetic diseases, which are characterized by developmental defects and/or cancer predisposition. In this review, we provide an overview of the roles and regulation of RECQL4 during maintenance of genome homeostasis. Full article
(This article belongs to the Special Issue Mechanisms of DNA Damage, Repair and Mutagenesis)
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23 pages, 7332 KiB  
Review
PCNA Loaders and Unloaders—One Ring That Rules Them All
by Matan Arbel, Karan Choudhary, Ofri Tfilin and Martin Kupiec
Genes 2021, 12(11), 1812; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12111812 - 18 Nov 2021
Cited by 20 | Viewed by 4225
Abstract
During each cell duplication, the entirety of the genomic DNA in every cell must be accurately and quickly copied. Given the short time available for the chore, the requirement of many proteins, and the daunting amount of DNA present, DNA replication poses a [...] Read more.
During each cell duplication, the entirety of the genomic DNA in every cell must be accurately and quickly copied. Given the short time available for the chore, the requirement of many proteins, and the daunting amount of DNA present, DNA replication poses a serious challenge to the cell. A high level of coordination between polymerases and other DNA and chromatin-interacting proteins is vital to complete this task. One of the most important proteins for maintaining such coordination is PCNA. PCNA is a multitasking protein that forms a homotrimeric ring that encircles the DNA. It serves as a processivity factor for DNA polymerases and acts as a landing platform for different proteins interacting with DNA and chromatin. Therefore, PCNA is a signaling hub that influences the rate and accuracy of DNA replication, regulates DNA damage repair, controls chromatin formation during the replication, and the proper segregation of the sister chromatids. With so many essential roles, PCNA recruitment and turnover on the chromatin is of utmost importance. Three different, conserved protein complexes are in charge of loading/unloading PCNA onto DNA. Replication factor C (RFC) is the canonical complex in charge of loading PCNA during the S-phase. The Ctf18 and Elg1 (ATAD5 in mammalian) proteins form complexes similar to RFC, with particular functions in the cell’s nucleus. Here we summarize our current knowledge about the roles of these important factors in yeast and mammals. Full article
(This article belongs to the Special Issue Mechanisms of DNA Damage, Repair and Mutagenesis)
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21 pages, 10418 KiB  
Review
Srs2 and Pif1 as Model Systems for Understanding Sf1a and Sf1b Helicase Structure and Function
by Aviv Meir and Eric C. Greene
Genes 2021, 12(9), 1319; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12091319 - 26 Aug 2021
Cited by 3 | Viewed by 2796
Abstract
Helicases are enzymes that convert the chemical energy stored in ATP into mechanical work, allowing them to move along and manipulate nucleic acids. The helicase superfamily 1 (Sf1) is one of the largest subgroups of helicases and they are required for a range [...] Read more.
Helicases are enzymes that convert the chemical energy stored in ATP into mechanical work, allowing them to move along and manipulate nucleic acids. The helicase superfamily 1 (Sf1) is one of the largest subgroups of helicases and they are required for a range of cellular activities across all domains of life. Sf1 helicases can be further subdivided into two classes called the Sf1a and Sf1b helicases, which move in opposite directions on nucleic acids. The results of this movement can range from the separation of strands within duplex nucleic acids to the physical remodeling or removal of nucleoprotein complexes. Here, we describe the characteristics of the Sf1a helicase Srs2 and the Sf1b helicase Pif1, both from the model organism Saccharomyces cerevisiae, focusing on the roles that they play in homologous recombination, a DNA repair pathway that is necessary for maintaining genome integrity. Full article
(This article belongs to the Special Issue Mechanisms of DNA Damage, Repair and Mutagenesis)
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18 pages, 4054 KiB  
Review
Hydroxyurea—The Good, the Bad and the Ugly
by Marcelina W. Musiałek and Dorota Rybaczek
Genes 2021, 12(7), 1096; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12071096 - 19 Jul 2021
Cited by 43 | Viewed by 10279
Abstract
Hydroxyurea (HU) is mostly referred to as an inhibitor of ribonucleotide reductase (RNR) and as the agent that is commonly used to arrest cells in the S-phase of the cycle by inducing replication stress. It is a well-known and widely used drug, one [...] Read more.
Hydroxyurea (HU) is mostly referred to as an inhibitor of ribonucleotide reductase (RNR) and as the agent that is commonly used to arrest cells in the S-phase of the cycle by inducing replication stress. It is a well-known and widely used drug, one which has proved to be effective in treating chronic myeloproliferative disorders and which is considered a staple agent in sickle anemia therapy and—recently—a promising factor in preventing cognitive decline in Alzheimer’s disease. The reversibility of HU-induced replication inhibition also makes it a common laboratory ingredient used to synchronize cell cycles. On the other hand, prolonged treatment or higher dosage of hydroxyurea causes cell death due to accumulation of DNA damage and oxidative stress. Hydroxyurea treatments are also still far from perfect and it has been suggested that it facilitates skin cancer progression. Also, recent studies have shown that hydroxyurea may affect a larger number of enzymes due to its less specific interaction mechanism, which may contribute to further as-yet unspecified factors affecting cell response. In this review, we examine the actual state of knowledge about hydroxyurea and the mechanisms behind its cytotoxic effects. The practical applications of the recent findings may prove to enhance the already existing use of the drug in new and promising ways. Full article
(This article belongs to the Special Issue Mechanisms of DNA Damage, Repair and Mutagenesis)
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15 pages, 2759 KiB  
Review
The Genome Stability Maintenance DNA Helicase DDX11 and Its Role in Cancer
by Mohammad Mahtab, Ana Boavida, Diana Santos and Francesca M. Pisani
Genes 2021, 12(3), 395; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12030395 - 10 Mar 2021
Cited by 9 | Viewed by 2660
Abstract
DDX11/ChlR1 is a super-family two iron–sulfur cluster containing DNA helicase with roles in DNA replication and sister chromatid cohesion establishment, and general chromosome architecture. Bi-allelic mutations of the DDX11 gene cause a rare hereditary disease, named Warsaw breakage syndrome, characterized by a complex [...] Read more.
DDX11/ChlR1 is a super-family two iron–sulfur cluster containing DNA helicase with roles in DNA replication and sister chromatid cohesion establishment, and general chromosome architecture. Bi-allelic mutations of the DDX11 gene cause a rare hereditary disease, named Warsaw breakage syndrome, characterized by a complex spectrum of clinical manifestations (pre- and post-natal growth defects, microcephaly, intellectual disability, heart anomalies and sister chromatid cohesion loss at cellular level) in accordance with the multifaceted, not yet fully understood, physiological functions of this DNA helicase. In the last few years, a possible role of DDX11 in the onset and progression of many cancers is emerging. Herein we summarize the results of recent studies, carried out either in tumoral cell lines or in xenograft cancer mouse models, suggesting that DDX11 may have an oncogenic role. The potential of DDX11 DNA helicase as a pharmacological target for novel anti-cancer therapeutic interventions, as inferred from these latest developments, is also discussed. Full article
(This article belongs to the Special Issue Mechanisms of DNA Damage, Repair and Mutagenesis)
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Review
The Amazing Acrobat: Yeast’s Histone H3K56 Juggles Several Important Roles While Maintaining Perfect Balance
by Lihi Gershon and Martin Kupiec
Genes 2021, 12(3), 342; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12030342 - 25 Feb 2021
Cited by 7 | Viewed by 2434
Abstract
Acetylation on lysine 56 of histone H3 of the yeast Saccharomyces cerevisiae has been implicated in many cellular processes that affect genome stability. Despite being the object of much research, the complete scope of the roles played by K56 acetylation is not fully [...] Read more.
Acetylation on lysine 56 of histone H3 of the yeast Saccharomyces cerevisiae has been implicated in many cellular processes that affect genome stability. Despite being the object of much research, the complete scope of the roles played by K56 acetylation is not fully understood even today. The acetylation is put in place at the S-phase of the cell cycle, in order to flag newly synthesized histones that are incorporated during DNA replication. The signal is removed by two redundant deacetylases, Hst3 and Hst4, at the entry to G2/M phase. Its crucial location, at the entry and exit points of the DNA into and out of the nucleosome, makes this a central modification, and dictates that if acetylation and deacetylation are not well concerted and executed in a timely fashion, severe genomic instability arises. In this review, we explore the wealth of information available on the many roles played by H3K56 acetylation and the deacetylases Hst3 and Hst4 in DNA replication and repair. Full article
(This article belongs to the Special Issue Mechanisms of DNA Damage, Repair and Mutagenesis)
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