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Mechanisms of Replication of Damaged DNA
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Mechanisms of Replication of Damaged DNA

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 June 2022) | Viewed by 12880

Special Issue Editors

Dr. Alena Makarova

E-Mail Website
Guest Editor
Institute of Molecular Genetics, National Research Center Kurchatov Institute, Moscow, Russia
Interests: DNA polymerases; DNA translesion synthesis; DNA damage
Prof. Dr. Youri I. Pavlov

E-Mail Website
Guest Editor
Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska, Omaha, NE, USA
Interests: mechanisms of maintenance of genomic stability during replication; repair; recombination; transcription and editing
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Tens of thousands of DNA lesions occur in eukaryotic cells each day due to various endogenous and environmental factors. Unrepaired DNA damage poses a threat to cells by blocking synthesis by replicative polymerases, causing killing and an elevated mutation frequency. Genetic studies in the mid-1970s demonstrated that the mutagenesis induced by DNA-damaging agents is an enzymatic process. The turn of the 20th and 21st centuries marked the discovery of specialized DNA polymerases capable of DNA translesion synthesis (TLS)—the mechanism of DNA damage tolerance.  The DNA polymerases Pol η, Pol ι, Pol κ, REV1, and Pol ζ efficiently incorporate nucleotides opposite a variety of DNA lesions and can extend mismatches during TLS. Several repair DNA polymerases (Pol β, Pol λ, Pol µ, and Pol θ) also possess TLS activity. In 2013, a new player involved in DNA damage tolerance was described—PrimPol, a DNA primase and DNA polymerase. PrimPol restarts stalled replication forks on the leading DNA strand by re-priming. The accuracy of specialized DNA polymerases is low compared to that of high-fidelity replicative DNA polymerases. TLS contributes to DNA damage tolerance but leads to the accumulation of mutations in genomic DNA and increases cancer risk. The activity of TLS enzymes decreases the efficacy of chemotherapy drugs blocking tumor cell division by damaging DNA.

This Special Issue will cover research on DNA damage tolerance and TLS mechanisms, the molecular basis of induced mutagenesis, and recent advances in biochemical and crystallographic studies of DNA polymerases. In this Special Issue of Genes, we welcome reviews, original research articles, and short communications. 

Dr. Alena Makarova
Prof. Youri I. Pavlov
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 lesions
  • Replication
  • DNA translesion synthesis
  • Mutagenesis
  • DNA Repair
  • DNA polymerases

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Published Papers (5 papers)

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Research

Jump to: Review

16 pages, 11701 KiB  
Article
DNA Polymerase ζ without the C-Terminus of Catalytic Subunit Rev3 Retains Characteristic Activity, but Alters Mutation Specificity of Ultraviolet Radiation in Yeast
by Hollie M. Siebler, Jian Cui, Sarah E. Hill and Youri I. Pavlov
Genes 2022, 13(9), 1576; https://doi.org/10.3390/genes13091576 - 2 Sep 2022
Cited by 1 | Viewed by 1827
Abstract
DNA polymerase ζ (pol ζ) plays a central role in replicating damaged genomic DNA. When DNA synthesis stalls at a lesion, it participates in translesion DNA synthesis (TLS), which helps replication proceed. TLS prevents cell death at the expense of new mutations. The [...] Read more.
DNA polymerase ζ (pol ζ) plays a central role in replicating damaged genomic DNA. When DNA synthesis stalls at a lesion, it participates in translesion DNA synthesis (TLS), which helps replication proceed. TLS prevents cell death at the expense of new mutations. The current model indicates that pol ζ-dependent TLS events are mediated by Pol31/Pol32 pol ζ subunits, which are shared with replicative polymerase pol δ. Surprisingly, we found that the mutant rev3-ΔC in yeast, which lacks the C-terminal domain (CTD) of the catalytic subunit of pol ζ and, thus, the platform for interaction with Pol31/Pol32, retains most pol ζ functions. To understand the underlying mechanisms, we studied TLS in normal templates or templates with abasic sites in vitro in primer extension reactions with purified four-subunit pol ζ versus pol ζ with Rev3-ΔC. We also examined the specificity of ultraviolet radiation (UVR)-induced mutagenesis in the rev3-ΔC strains. We found that the absence of Rev3 CTD reduces activity levels, but does not alter the basic biochemical properties of pol ζ, and alters the mutation spectrum only at high doses of UVR, alluding to the existence of mechanisms of recruitment of pol ζ to UVR-damaged sites independent of the interaction of Pol31/Pol32 with the CTD of Rev3. Full article
(This article belongs to the Special Issue Mechanisms of Replication of Damaged DNA)
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15 pages, 2795 KiB  
Article
Stalling of Eukaryotic Translesion DNA Polymerases at DNA-Protein Cross-Links
by Anna V. Yudkina, Evgeniy S. Shilkin, Alena V. Makarova and Dmitry O. Zharkov
Genes 2022, 13(2), 166; https://doi.org/10.3390/genes13020166 - 18 Jan 2022
Cited by 6 | Viewed by 2381
Abstract
DNA-protein cross-links (DPCs) are extremely bulky adducts that interfere with replication. In human cells, they are processed by SPRTN, a protease activated by DNA polymerases stuck at DPCs. We have recently proposed the mechanism of the interaction of DNA polymerases with DPCs, involving [...] Read more.
DNA-protein cross-links (DPCs) are extremely bulky adducts that interfere with replication. In human cells, they are processed by SPRTN, a protease activated by DNA polymerases stuck at DPCs. We have recently proposed the mechanism of the interaction of DNA polymerases with DPCs, involving a clash of protein surfaces followed by the distortion of the cross-linked protein. Here, we used a model DPC, located in the single-stranded template, the template strand of double-stranded DNA, or the displaced strand, to study the eukaryotic translesion DNA polymerases ζ (POLζ), ι (POLι) and η (POLη). POLι demonstrated poor synthesis on the DPC-containing substrates. POLζ and POLη paused at sites dictated by the footprints of the polymerase and the cross-linked protein. Beyond that, POLζ was able to elongate the primer to the cross-link site when a DPC was in the template. Surprisingly, POLη was not only able to reach the cross-link site but also incorporated 1–2 nucleotides past it, which makes POLη the most efficient DNA polymerase on DPC-containing substrates. However, a DPC in the displaced strand was an insurmountable obstacle for all polymerases, which stalled several nucleotides before the cross-link site. Overall, the behavior of translesion polymerases agrees with the model of protein clash and distortion described above. Full article
(This article belongs to the Special Issue Mechanisms of Replication of Damaged DNA)
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17 pages, 1859 KiB  
Article
Human PrimPol Discrimination against Dideoxynucleotides during Primer Synthesis
by Gustavo Carvalho, Alberto Díaz-Talavera, Patricia A. Calvo, Luis Blanco and María I. Martínez-Jiménez
Genes 2021, 12(10), 1487; https://doi.org/10.3390/genes12101487 - 24 Sep 2021
Cited by 6 | Viewed by 2371
Abstract
PrimPol is required to re-prime DNA replication at both nucleus and mitochondria, thus facilitating fork progression during replicative stress. ddC is a chain-terminating nucleotide that has been widely used to block mitochondrial DNA replication because it is efficiently incorporated by the replicative polymerase [...] Read more.
PrimPol is required to re-prime DNA replication at both nucleus and mitochondria, thus facilitating fork progression during replicative stress. ddC is a chain-terminating nucleotide that has been widely used to block mitochondrial DNA replication because it is efficiently incorporated by the replicative polymerase Polγ. Here, we show that human PrimPol discriminates against dideoxynucleotides (ddNTP) when elongating a primer across 8oxoG lesions in the template, but also when starting de novo synthesis of DNA primers, and especially when selecting the 3′nucleotide of the initial dimer. PrimPol incorporates ddNTPs with a very low efficiency compared to dNTPs even in the presence of activating manganese ions, and only a 40-fold excess of ddNTP would significantly disturb PrimPol primase activity. This discrimination against ddNTPs prevents premature termination of the primers, warranting their use for elongation. The crystal structure of human PrimPol highlights Arg291 residue as responsible for the strong dNTP/ddNTP selectivity, since it interacts with the 3′-OH group of the incoming deoxynucleotide, absent in ddNTPs. Arg291, shown here to be critical for both primase and polymerase activities of human PrimPol, would contribute to the preferred binding of dNTPs versus ddNTPs at the 3′elongation site, thus avoiding synthesis of abortive primers. Full article
(This article belongs to the Special Issue Mechanisms of Replication of Damaged DNA)
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Review

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13 pages, 2144 KiB  
Review
Recent Advances in Understanding the Structures of Translesion Synthesis DNA Polymerases
by Justin A. Ling, Zach Frevert and M. Todd Washington
Genes 2022, 13(5), 915; https://doi.org/10.3390/genes13050915 - 20 May 2022
Cited by 4 | Viewed by 2565
Abstract
DNA damage in the template strand causes replication forks to stall because replicative DNA polymerases are unable to efficiently incorporate nucleotides opposite template DNA lesions. To overcome these replication blocks, cells are equipped with multiple translesion synthesis polymerases that have evolved specifically to [...] Read more.
DNA damage in the template strand causes replication forks to stall because replicative DNA polymerases are unable to efficiently incorporate nucleotides opposite template DNA lesions. To overcome these replication blocks, cells are equipped with multiple translesion synthesis polymerases that have evolved specifically to incorporate nucleotides opposite DNA lesions. Over the past two decades, X-ray crystallography has provided a wealth of information about the structures and mechanisms of translesion synthesis polymerases. This approach, however, has been limited to ground state structures of these polymerases bound to DNA and nucleotide substrates. Three recent methodological developments have extended our understanding of the structures and mechanisms of these polymerases. These include time-lapse X-ray crystallography, which allows one to identify novel reaction intermediates; full-ensemble hybrid methods, which allow one to examine the conformational flexibility of the intrinsically disordered regions of proteins; and cryo-electron microscopy, which allows one to determine the high-resolution structures of larger protein complexes. In this article, we will discuss how these three methodological developments have added to our understanding of the structures and mechanisms of translesion synthesis polymerases. Full article
(This article belongs to the Special Issue Mechanisms of Replication of Damaged DNA)
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19 pages, 6831 KiB  
Review
Structural Insights into the Specificity of 8-Oxo-7,8-dihydro-2′-deoxyguanosine Bypass by Family X DNA Polymerases
by Andrea M. Kaminski, Thomas A. Kunkel, Lars C. Pedersen and Katarzyna Bebenek
Genes 2022, 13(1), 15; https://doi.org/10.3390/genes13010015 - 22 Dec 2021
Cited by 3 | Viewed by 2672
Abstract
8-oxo-guanine (8OG) is a common base lesion, generated by reactive oxygen species, which has been associated with human diseases such as cancer, aging-related neurodegenerative disorders and atherosclerosis. 8OG is highly mutagenic, due to its dual-coding potential it can pair both with adenine or [...] Read more.
8-oxo-guanine (8OG) is a common base lesion, generated by reactive oxygen species, which has been associated with human diseases such as cancer, aging-related neurodegenerative disorders and atherosclerosis. 8OG is highly mutagenic, due to its dual-coding potential it can pair both with adenine or cytidine. Therefore, it creates a challenge for DNA polymerases striving to correctly replicate and/or repair genomic or mitochondrial DNA. Numerous structural studies provide insights into the mechanistic basis of the specificity of 8OG bypass by DNA polymerases from different families. Here, we focus on how repair polymerases from Family X (Pols β, λ and µ) engage DNA substrates containing the oxidized guanine. We review structures of binary and ternary complexes for the three polymerases, which represent distinct steps in their catalytic cycles—the binding of the DNA substrate and the incoming nucleotide, followed by its insertion and extension. At each of these steps, the polymerase may favor or exclude the correct C or incorrect A, affecting the final outcome, which varies depending on the enzyme. Full article
(This article belongs to the Special Issue Mechanisms of Replication of Damaged DNA)
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