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Recent Advances in Genome Maintenance Studies
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Recent Advances in Genome Maintenance Studies

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biophysics".

Deadline for manuscript submissions: closed (30 November 2023) | Viewed by 18157

Special Issue Editor

Dr. Ingrid Tessmer

E-Mail Website
Guest Editor
Rudolf Virchow Center for Integrative and Translational Bioimaging, Josef Schneider Str. 2, 97080 Würzburg, Germany
Interests: DNA repair; genome maintenance; single molecule studies

Special Issue Information

Dear Colleagues,

Genome maintenance is vitally important for cellular viability. The DNA inside cells is continuously damaged by endogenous as well as exogenous factors (such as metabolic products or high energy radiation, respectively) and the resulting lesions in the DNA need to be rapidly and efficiently repaired by dedicated DNA repair protein systems to prevent mutagenesis and cell death. Mutations in DNA also result from DNA lesion bypass by DNA polymerases that can prevent fatal replication fork collapse during duplication of the genome for cell division, but comes at the cost of being error prone. In addition, epigenetic marks need to be maintained and faithfully introduced into newly synthesized DNA to ensure correct gene transcription. Finally, 3D organization of DNA and chromatin remodeling during transcription and replication require positional precision and accurate timing. All these processes are achieved via carefully controlled protein-DNA interactions. Recent methodological advances have tremendously profited studies of the underlying protein-DNA interactions. In addition to studies on human enzymes, molecular level studies on simpler systems such as bacteria or viruses have also brought invaluable novel insight for a clearer picture of the mechanisms and regulation of these DNA maintenance systems.

Authors are invited to submit original research and review articles, which address the progress in our understanding of genome maintenance processes at the molecular level.

Topics include, but are not limited to:

  • DNA repair
  • DNA replication
  • Epigenetic regulation
  • Chromatin remodeling
  • Novel methodologies for protein-DNA interaction studies

Dr. Ingrid Tessmer
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. 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.

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Further information on MDPI's Special Issue polices can be found here.

Published Papers (9 papers)

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Editorial

Jump to: Research, Review

3 pages, 152 KiB  
Editorial
Recent Advances in Genome Maintenance Processes
by Ingrid Tessmer
Int. J. Mol. Sci. 2024, 25(10), 5131; https://doi.org/10.3390/ijms25105131 - 9 May 2024
Viewed by 1042
Abstract
Given life’s dependence on genome maintenance, unsurprisingly, investigations of the molecular processes involved in protecting the genome or, failing this, repairing damages to and alterations introduced into genetic material are at the forefront of current research [...] Full article
(This article belongs to the Special Issue Recent Advances in Genome Maintenance Studies)

Research

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20 pages, 6525 KiB  
Article
The Role of Key Amino Acids of the Human Fe(II)/2OG-Dependent Dioxygenase ALKBH3 in Structural Dynamics and Repair Activity toward Methylated DNA
by Lyubov Yu. Kanazhevskaya, Alexey A. Gorbunov, Maria V. Lukina, Denis A. Smyshliaev, Polina V. Zhdanova, Alexander A. Lomzov and Vladimir V. Koval
Int. J. Mol. Sci. 2024, 25(2), 1145; https://doi.org/10.3390/ijms25021145 - 17 Jan 2024
Viewed by 1380
Abstract
Non-heme dioxygenases of the AlkB family hold a unique position among enzymes that repair alkyl lesions in nucleic acids. These enzymes activate the Fe(II) ion and molecular oxygen through the coupled decarboxylation of the 2-oxoglutarate co-substrate to subsequently oxidize the substrate. ALKBH3 is [...] Read more.
Non-heme dioxygenases of the AlkB family hold a unique position among enzymes that repair alkyl lesions in nucleic acids. These enzymes activate the Fe(II) ion and molecular oxygen through the coupled decarboxylation of the 2-oxoglutarate co-substrate to subsequently oxidize the substrate. ALKBH3 is a human homolog of E. coli AlkB, which displays a specific activity toward N1-methyladenine and N3-methylcytosine bases in single-stranded DNA. Due to the lack of a DNA-bound structure of ALKBH3, the basis of its substrate specificity and structure–function relationships requires further exploration. Here we have combined biochemical and biophysical approaches with site-directed mutational analysis to elucidate the role of key amino acids in maintaining the secondary structure and catalytic activity of ALKBH3. Using stopped-flow fluorescence spectroscopy we have shown that conformational dynamics play a crucial role in the catalytic repair process catalyzed by ALKBH3. A transient kinetic mechanism, which comprises the steps of the specific substrate binding, eversion, and anchoring within the DNA-binding cleft, has been described quantitatively by rate and equilibrium constants. Through CD spectroscopy, we demonstrated that replacing side chains of Tyr143, Leu177, and His191 with alanine results in significant alterations in the secondary structure content of ALKBH3 and decreases the stability of mutant proteins. The bulky side chain of Tyr143 is critical for binding the methylated base and stabilizing its flipped-out conformation, while its hydroxyl group is likely involved in facilitating the product release. The removal of the Leu177 and His191 side chains substantially affects the secondary structure content and conformational flexibility, leading to the complete inactivation of the protein. The mutants lacking enzymatic activity exhibit a marked decrease in antiparallel β-strands, offset by an increase in the helical component. Full article
(This article belongs to the Special Issue Recent Advances in Genome Maintenance Studies)
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18 pages, 1592 KiB  
Article
Correlated Target Search by Vaccinia Virus Uracil–DNA Glycosylase, a DNA Repair Enzyme and a Processivity Factor of Viral Replication Machinery
by Evgeniia A. Diatlova, Grigory V. Mechetin, Anna V. Yudkina, Vasily D. Zharkov, Natalia A. Torgasheva, Anton V. Endutkin, Olga V. Shulenina, Andrey L. Konevega, Irina P. Gileva, Sergei N. Shchelkunov and Dmitry O. Zharkov
Int. J. Mol. Sci. 2023, 24(11), 9113; https://doi.org/10.3390/ijms24119113 - 23 May 2023
Viewed by 1560
Abstract
The protein encoded by the vaccinia virus D4R gene has base excision repair uracil–DNA N-glycosylase (vvUNG) activity and also acts as a processivity factor in the viral replication complex. The use of a protein unlike PolN/PCNA sliding clamps is a unique feature [...] Read more.
The protein encoded by the vaccinia virus D4R gene has base excision repair uracil–DNA N-glycosylase (vvUNG) activity and also acts as a processivity factor in the viral replication complex. The use of a protein unlike PolN/PCNA sliding clamps is a unique feature of orthopoxviral replication, providing an attractive target for drug design. However, the intrinsic processivity of vvUNG has never been estimated, leaving open the question whether it is sufficient to impart processivity to the viral polymerase. Here, we use the correlated cleavage assay to characterize the translocation of vvUNG along DNA between two uracil residues. The salt dependence of the correlated cleavage, together with the similar affinity of vvUNG for damaged and undamaged DNA, support the one-dimensional diffusion mechanism of lesion search. Unlike short gaps, covalent adducts partly block vvUNG translocation. Kinetic experiments show that once a lesion is found it is excised with a probability ~0.76. Varying the distance between two uracils, we use a random walk model to estimate the mean number of steps per association with DNA at ~4200, which is consistent with vvUNG playing a role as a processivity factor. Finally, we show that inhibitors carrying a tetrahydro-2,4,6-trioxopyrimidinylidene moiety can suppress the processivity of vvUNG. Full article
(This article belongs to the Special Issue Recent Advances in Genome Maintenance Studies)
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Review

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19 pages, 2675 KiB  
Review
DNA Repair in Nucleosomes: Insights from Histone Modifications and Mutants
by Kathiresan Selvam, John J. Wyrick and Michael A. Parra
Int. J. Mol. Sci. 2024, 25(8), 4393; https://doi.org/10.3390/ijms25084393 - 16 Apr 2024
Cited by 1 | Viewed by 1716
Abstract
DNA repair pathways play a critical role in genome stability, but in eukaryotic cells, they must operate to repair DNA lesions in the compact and tangled environment of chromatin. Previous studies have shown that the packaging of DNA into nucleosomes, which form the [...] Read more.
DNA repair pathways play a critical role in genome stability, but in eukaryotic cells, they must operate to repair DNA lesions in the compact and tangled environment of chromatin. Previous studies have shown that the packaging of DNA into nucleosomes, which form the basic building block of chromatin, has a profound impact on DNA repair. In this review, we discuss the principles and mechanisms governing DNA repair in chromatin. We focus on the role of histone post-translational modifications (PTMs) in repair, as well as the molecular mechanisms by which histone mutants affect cellular sensitivity to DNA damage agents and repair activity in chromatin. Importantly, these mechanisms are thought to significantly impact somatic mutation rates in human cancers and potentially contribute to carcinogenesis and other human diseases. For example, a number of the histone mutants studied primarily in yeast have been identified as candidate oncohistone mutations in different cancers. This review highlights these connections and discusses the potential importance of DNA repair in chromatin to human health. Full article
(This article belongs to the Special Issue Recent Advances in Genome Maintenance Studies)
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20 pages, 2419 KiB  
Review
Replication Protein A, the Main Eukaryotic Single-Stranded DNA Binding Protein, a Focal Point in Cellular DNA Metabolism
by Heinz Peter Nasheuer, Anna Marie Meaney, Timothy Hulshoff, Ines Thiele and Nichodemus O. Onwubiko
Int. J. Mol. Sci. 2024, 25(1), 588; https://doi.org/10.3390/ijms25010588 - 2 Jan 2024
Cited by 4 | Viewed by 2845
Abstract
Replication protein A (RPA) is a heterotrimeric protein complex and the main single-stranded DNA (ssDNA)-binding protein in eukaryotes. RPA has key functions in most of the DNA-associated metabolic pathways and DNA damage signalling. Its high affinity for ssDNA helps to stabilise ssDNA structures [...] Read more.
Replication protein A (RPA) is a heterotrimeric protein complex and the main single-stranded DNA (ssDNA)-binding protein in eukaryotes. RPA has key functions in most of the DNA-associated metabolic pathways and DNA damage signalling. Its high affinity for ssDNA helps to stabilise ssDNA structures and protect the DNA sequence from nuclease attacks. RPA consists of multiple DNA-binding domains which are oligonucleotide/oligosaccharide-binding (OB)-folds that are responsible for DNA binding and interactions with proteins. These RPA–ssDNA and RPA–protein interactions are crucial for DNA replication, DNA repair, DNA damage signalling, and the conservation of the genetic information of cells. Proteins such as ATR use RPA to locate to regions of DNA damage for DNA damage signalling. The recruitment of nucleases and DNA exchange factors to sites of double-strand breaks are also an important RPA function to ensure effective DNA recombination to correct these DNA lesions. Due to its high affinity to ssDNA, RPA’s removal from ssDNA is of central importance to allow these metabolic pathways to proceed, and processes to exchange RPA against downstream factors are established in all eukaryotes. These faceted and multi-layered functions of RPA as well as its role in a variety of human diseases will be discussed. Full article
(This article belongs to the Special Issue Recent Advances in Genome Maintenance Studies)
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28 pages, 3045 KiB  
Review
The DNA Alkyltransferase Family of DNA Repair Proteins: Common Mechanisms, Diverse Functions
by Ingrid Tessmer and Geoffrey P. Margison
Int. J. Mol. Sci. 2024, 25(1), 463; https://doi.org/10.3390/ijms25010463 - 29 Dec 2023
Cited by 2 | Viewed by 1173
Abstract
DNA alkyltransferase and alkyltransferase-like family proteins are responsible for the repair of highly mutagenic and cytotoxic O6-alkylguanine and O4-alkylthymine bases in DNA. Their mechanism involves binding to the damaged DNA and flipping the base out of the DNA helix [...] Read more.
DNA alkyltransferase and alkyltransferase-like family proteins are responsible for the repair of highly mutagenic and cytotoxic O6-alkylguanine and O4-alkylthymine bases in DNA. Their mechanism involves binding to the damaged DNA and flipping the base out of the DNA helix into the active site pocket in the protein. Alkyltransferases then directly and irreversibly transfer the alkyl group from the base to the active site cysteine residue. In contrast, alkyltransferase-like proteins recruit nucleotide excision repair components for O6-alkylguanine elimination. One or more of these proteins are found in all kingdoms of life, and where this has been determined, their overall DNA repair mechanism is strictly conserved between organisms. Nevertheless, between species, subtle as well as more extensive differences that affect target lesion preferences and/or introduce additional protein functions have evolved. Examining these differences and their functional consequences is intricately entwined with understanding the details of their DNA repair mechanism(s) and their biological roles. In this review, we will present and discuss various aspects of the current status of knowledge on this intriguing protein family. Full article
(This article belongs to the Special Issue Recent Advances in Genome Maintenance Studies)
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20 pages, 761 KiB  
Review
Macromolecular Crowding and DNA: Bridging the Gap between In Vitro and In Vivo
by Dylan Collette, David Dunlap and Laura Finzi
Int. J. Mol. Sci. 2023, 24(24), 17502; https://doi.org/10.3390/ijms242417502 - 15 Dec 2023
Cited by 6 | Viewed by 2481
Abstract
The cellular environment is highly crowded, with up to 40% of the volume fraction of the cell occupied by various macromolecules. Most laboratory experiments take place in dilute buffer solutions; by adding various synthetic or organic macromolecules, researchers have begun to bridge the [...] Read more.
The cellular environment is highly crowded, with up to 40% of the volume fraction of the cell occupied by various macromolecules. Most laboratory experiments take place in dilute buffer solutions; by adding various synthetic or organic macromolecules, researchers have begun to bridge the gap between in vitro and in vivo measurements. This is a review of the reported effects of macromolecular crowding on the compaction and extension of DNA, the effect of macromolecular crowding on DNA kinetics, and protein-DNA interactions. Theoretical models related to macromolecular crowding and DNA are briefly reviewed. Gaps in the literature, including the use of biologically relevant crowders, simultaneous use of multi-sized crowders, empirical connections between macromolecular crowding and liquid–liquid phase separation of nucleic materials are discussed. Full article
(This article belongs to the Special Issue Recent Advances in Genome Maintenance Studies)
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18 pages, 3093 KiB  
Review
UV-DDB as a General Sensor of DNA Damage in Chromatin: Multifaceted Approaches to Assess Its Direct Role in Base Excision Repair
by Sripriya J. Raja and Bennett Van Houten
Int. J. Mol. Sci. 2023, 24(12), 10168; https://doi.org/10.3390/ijms241210168 - 15 Jun 2023
Viewed by 2146
Abstract
Base excision repair (BER) is a cellular process that removes damaged bases arising from exogenous and endogenous sources including reactive oxygen species, alkylation agents, and ionizing radiation. BER is mediated by the actions of multiple proteins which work in a highly concerted manner [...] Read more.
Base excision repair (BER) is a cellular process that removes damaged bases arising from exogenous and endogenous sources including reactive oxygen species, alkylation agents, and ionizing radiation. BER is mediated by the actions of multiple proteins which work in a highly concerted manner to resolve DNA damage efficiently to prevent toxic repair intermediates. During the initiation of BER, the damaged base is removed by one of 11 mammalian DNA glycosylases, resulting in abasic sites. Many DNA glycosylases are product-inhibited by binding to the abasic site more avidly than the damaged base. Traditionally, apurinic/apyrimidinic endonuclease 1, APE1, was believed to help turn over the glycosylases to undergo multiple rounds of damaged base removal. However, in a series of papers from our laboratory, we have demonstrated that UV-damaged DNA binding protein (UV-DDB) stimulates the glycosylase activities of human 8-oxoguanine glycosylase (OGG1), MUTY DNA glycosylase (MUTYH), alkyladenine glycosylase/N-methylpurine DNA glycosylase (AAG/MPG), and single-strand selective monofunctional glycosylase (SMUG1), between three- and five-fold. Moreover, we have shown that UV-DDB can assist chromatin decompaction, facilitating access of OGG1 to 8-oxoguanine damage in telomeres. This review summarizes the biochemistry, single-molecule, and cell biology approaches that our group used to directly demonstrate the essential role of UV-DDB in BER. Full article
(This article belongs to the Special Issue Recent Advances in Genome Maintenance Studies)
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19 pages, 2415 KiB  
Review
Contribution of Microhomology to Genome Instability: Connection between DNA Repair and Replication Stress
by Yuning Jiang
Int. J. Mol. Sci. 2022, 23(21), 12937; https://doi.org/10.3390/ijms232112937 - 26 Oct 2022
Cited by 6 | Viewed by 2984
Abstract
Microhomology-mediated end joining (MMEJ) is a highly mutagenic pathway to repair double-strand breaks (DSBs). MMEJ was thought to be a backup pathway of homologous recombination (HR) and canonical nonhomologous end joining (C-NHEJ). However, it attracts more attention in cancer research due to its [...] Read more.
Microhomology-mediated end joining (MMEJ) is a highly mutagenic pathway to repair double-strand breaks (DSBs). MMEJ was thought to be a backup pathway of homologous recombination (HR) and canonical nonhomologous end joining (C-NHEJ). However, it attracts more attention in cancer research due to its special function of microhomology in many different aspects of cancer. In particular, it is initiated with DNA end resection and upregulated in homologous recombination-deficient cancers. In this review, I summarize the following: (1) the recent findings and contributions of MMEJ to genome instability, including phenotypes relevant to MMEJ; (2) the interaction between MMEJ and other DNA repair pathways; (3) the proposed mechanistic model of MMEJ in DNA DSB repair and a new connection with microhomology-mediated break-induced replication (MMBIR); and (4) the potential clinical application by targeting MMEJ based on synthetic lethality for cancer therapy. Full article
(This article belongs to the Special Issue Recent Advances in Genome Maintenance Studies)
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