The Key of DNA Recombination and Replication—Recombination Mediator Proteins

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

Deadline for manuscript submissions: closed (25 May 2021) | Viewed by 26771

Special Issue Editors


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Guest Editor
E.A.Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, 1100 S. Grand blvd., DRC 513, St. Louis, MO 63104, USA
Interests: structural biology; DNA repair; recombiation mediator protein; cancer; drug design

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Guest Editor
1. Institut Curie, PSL University, CNRS, UMR3348, 91400 Orsay, France
2. Paris-Saclay University CNRS, UMR3348, 91400 Orsay, France

Special Issue Information

Dear Colleagues,

Recombination mediator proteins (RMPs) regulate homologous recombination (HR), an essential pathway to preserve chromosome integrity and generate genetic diversity. HR is involved in a plethora of diverse chromosome metabolic events and must be tightly regulated to prevent the deleterious consequences of hypo- or hyperrecombination. The highly elaborate mechanism of HR is strictly conserved. The two main eukaryotic homologous recombination proteins, Rad51 and Dmc1, display similar structure to RecA, the single homologous recombination protein in prokaryotes. The regulation of their activity and specificity in the vastly diverse transactions they mediate is achieved via multiple specialized proteins including ubiquitous RMPs. RMP structures are highly diverse and their complexity dramatically increases throughout the evolutionary tree. Among their different functions, RMPs support the repair of various DNA aberrations, including the most deleterious DNA double-strand breaks, participate in inter-strand crosslink repair and replicative lesions, support telomere maintenance and ensure proper chromosome segregation. Major human RMPs include three tumor suppressors, breast cancer susceptibility proteins 1 and 2 (BRCA1, -2) and partner and localizer of BRCA2 protein (PALB2) as well as RAD51 paralogs, the mutations of which predispose to breast, ovarian and other cancers and are at the beginning of severe forms of Fanconi anemia. By supporting high-fidelity DNA repair, RMPs counteract DNA damage-based therapy and can lead to drug resistance. Rad52 is a major RMP in S. cerevisiae and RecFOR proteins are most common RMPs in bacteria. Although they do not share sequence or structural homology, these factors support exquisitely conserved HR activity during the repair of chromosome breaks and at stalled replication forks. Intriguingly, several unrelated RMPs support similar recombinase-independent functions, e.g., strand annealing. Numerous accessory factors and modulators of HR, e.g., RecBCD helicase, Rad54, Rad51 paralogs, ssDNA binding proteins SSB and RPA and antirecombinase helicases further contribute to the fine-tuning of HR in both prokaryotes and eukaryotes.

This Special Issue will include manuscripts describing molecular mechanisms, physiological functions and associated pathologies of RMPs across different species. We expect that this compilation of articles elaborated by experts in the field will foster discussion and add insights into the mechanisms and functions of HR supported by RMPs. This Special Issue will also contribute to the understanding of the etiology of related diseases, such as cancer or neurodegeneration, and of drug resistance. Finally, we hope our joint efforts will promote the discovery of novel therapeutic approaches.

Dr. Sergey Korolev
Dr. Aura Carreira
Guest Editors

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Keywords

  • Homologous recombination 
  • DNA repair 
  • Replication repair 
  • DNA protein interaction 
  • Protein scaffold 
  • Cancer predisposition 
  • Drug design 
  • Telomere maintenance

Published Papers (7 papers)

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Research

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12 pages, 2336 KiB  
Article
Structural Insight into the Mechanism of PALB2 Interaction with MRG15
by Jennifer Redington, Jaigeeth Deveryshetty, Lakshmi Kanikkannan, Ian Miller and Sergey Korolev
Genes 2021, 12(12), 2002; https://doi.org/10.3390/genes12122002 - 17 Dec 2021
Cited by 4 | Viewed by 2915
Abstract
The tumor suppressor protein partner and localizer of BRCA2 (PALB2) orchestrates the interactions between breast cancer susceptibility proteins 1 and 2 (BRCA1, -2) that are critical for genome stability, homologous recombination (HR) and DNA repair. PALB2 mutations predispose patients to a spectrum of [...] Read more.
The tumor suppressor protein partner and localizer of BRCA2 (PALB2) orchestrates the interactions between breast cancer susceptibility proteins 1 and 2 (BRCA1, -2) that are critical for genome stability, homologous recombination (HR) and DNA repair. PALB2 mutations predispose patients to a spectrum of cancers, including breast and ovarian cancers. PALB2 localizes HR machinery to chromatin and links it with transcription through multiple DNA and protein interactions. This includes its interaction with MRG15 (Morf-related gene on chromosome 15), which is part of many transcription complexes, including the HAT-associated and the HDAC-associated complexes. This interaction is critical for PALB2 localization in actively transcribed genes, where transcription/replication conflicts lead to frequent replication stress and DNA breaks. We solved the crystal structure of the MRG15 MRG domain bound to the PALB2 peptide and investigated the effect of several PALB2 mutations, including patient-derived variants. PALB2 interacts with an extended surface of the MRG that is known to interact with other proteins. This, together with a nanomolar affinity, suggests that the binding of MRG15 partners, including PALB2, to this region is mutually exclusive. Breast cancer-related mutations of PALB2 cause only minor attenuation of the binding affinity. New data reveal the mechanism of PALB2-MRG15 binding, advancing our understanding of PALB2 function in chromosome maintenance and tumorigenesis. Full article
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21 pages, 3808 KiB  
Article
New RAD51 Inhibitors to Target Homologous Recombination in Human Cells
by Irina S. Shkundina, Alexander A. Gall, Alexej Dick, Simon Cocklin and Alexander V. Mazin
Genes 2021, 12(6), 920; https://doi.org/10.3390/genes12060920 - 16 Jun 2021
Cited by 21 | Viewed by 4730
Abstract
Targeting DNA repair proteins with small-molecule inhibitors became a proven anti-cancer strategy. Previously, we identified an inhibitor of a major protein of homologous recombination (HR) RAD51, named B02. B02 inhibited HR in human cells and sensitized them to chemotherapeutic drugs in vitro and [...] Read more.
Targeting DNA repair proteins with small-molecule inhibitors became a proven anti-cancer strategy. Previously, we identified an inhibitor of a major protein of homologous recombination (HR) RAD51, named B02. B02 inhibited HR in human cells and sensitized them to chemotherapeutic drugs in vitro and in vivo. Here, using a medicinal chemistry approach, we aimed to improve the potency of B02. We identified the B02 analog, B02-isomer, which inhibits HR in human cells with significantly higher efficiency. We also show that B02-iso sensitizes triple-negative breast cancer MDA-MB-231 cells to the PARP inhibitor (PARPi) olaparib. Full article
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Review

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29 pages, 5599 KiB  
Review
Recombination Mediator Proteins: Misnomers That Are Key to Understanding the Genomic Instabilities in Cancer
by Justin Courcelle, Travis K. Worley and Charmain T. Courcelle
Genes 2022, 13(3), 437; https://doi.org/10.3390/genes13030437 - 27 Feb 2022
Cited by 3 | Viewed by 2287
Abstract
Recombination mediator proteins have come into focus as promising targets for cancer therapy, with synthetic lethal approaches now clinically validated by the efficacy of PARP inhibitors in treating BRCA2 cancers and RECQ inhibitors in treating cancers with microsatellite instabilities. Thus, understanding the cellular [...] Read more.
Recombination mediator proteins have come into focus as promising targets for cancer therapy, with synthetic lethal approaches now clinically validated by the efficacy of PARP inhibitors in treating BRCA2 cancers and RECQ inhibitors in treating cancers with microsatellite instabilities. Thus, understanding the cellular role of recombination mediators is critically important, both to improve current therapies and develop new ones that target these pathways. Our mechanistic understanding of BRCA2 and RECQ began in Escherichia coli. Here, we review the cellular roles of RecF and RecQ, often considered functional homologs of these proteins in bacteria. Although these proteins were originally isolated as genes that were required during replication in sexual cell cycles that produce recombinant products, we now know that their function is similarly required during replication in asexual or mitotic-like cell cycles, where recombination is detrimental and generally not observed. Cells mutated in these gene products are unable to protect and process replication forks blocked at DNA damage, resulting in high rates of cell lethality and recombination events that compromise genome integrity during replication. Full article
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17 pages, 2187 KiB  
Review
Homologous Recombination as a Fundamental Genome Surveillance Mechanism during DNA Replication
by Julian Spies, Hana Polasek-Sedlackova, Jiri Lukas and Kumar Somyajit
Genes 2021, 12(12), 1960; https://doi.org/10.3390/genes12121960 - 9 Dec 2021
Cited by 16 | Viewed by 5519
Abstract
Accurate and complete genome replication is a fundamental cellular process for the proper transfer of genetic material to cell progenies, normal cell growth, and genome stability. However, a plethora of extrinsic and intrinsic factors challenge individual DNA replication forks and cause replication stress [...] Read more.
Accurate and complete genome replication is a fundamental cellular process for the proper transfer of genetic material to cell progenies, normal cell growth, and genome stability. However, a plethora of extrinsic and intrinsic factors challenge individual DNA replication forks and cause replication stress (RS), a hallmark of cancer. When challenged by RS, cells deploy an extensive range of mechanisms to safeguard replicating genomes and limit the burden of DNA damage. Prominent among those is homologous recombination (HR). Although fundamental to cell division, evidence suggests that cancer cells exploit and manipulate these RS responses to fuel their evolution and gain resistance to therapeutic interventions. In this review, we focused on recent insights into HR-mediated protection of stress-induced DNA replication intermediates, particularly the repair and protection of daughter strand gaps (DSGs) that arise from discontinuous replication across a damaged DNA template. Besides mechanistic underpinnings of this process, which markedly differ depending on the extent and duration of RS, we highlight the pathophysiological scenarios where DSG repair is naturally silenced. Finally, we discuss how such pathophysiological events fuel rampant mutagenesis, promoting cancer evolution, but also manifest in adaptative responses that can be targeted for cancer therapy. Full article
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14 pages, 755 KiB  
Review
Non-Recombinogenic Functions of Rad51, BRCA2, and Rad52 in DNA Damage Tolerance
by Félix Prado
Genes 2021, 12(10), 1550; https://doi.org/10.3390/genes12101550 - 29 Sep 2021
Cited by 6 | Viewed by 3516
Abstract
The DNA damage tolerance (DDT) response is aimed to timely and safely complete DNA replication by facilitating the advance of replication forks through blocking lesions. This process is associated with an accumulation of single-strand DNA (ssDNA), both at the fork and behind the [...] Read more.
The DNA damage tolerance (DDT) response is aimed to timely and safely complete DNA replication by facilitating the advance of replication forks through blocking lesions. This process is associated with an accumulation of single-strand DNA (ssDNA), both at the fork and behind the fork. Lesion bypass and ssDNA filling can be performed by translation synthesis (TLS) and template switching mechanisms. TLS uses low-fidelity polymerases to incorporate a dNTP opposite the blocking lesion, whereas template switching uses a Rad51/ssDNA nucleofilament and the sister chromatid to bypass the lesion. Rad51 is loaded at this nucleofilament by two mediator proteins, BRCA2 and Rad52, and these three factors are critical for homologous recombination (HR). Here, we review recent advances showing that Rad51, BRCA2, and Rad52 perform some of these functions through mechanisms that do not require the strand exchange activity of Rad51: the formation and protection of reversed fork structures aimed to bypass blocking lesions, and the promotion of TLS. These findings point to the central HR proteins as potential molecular switches in the choice of the mechanism of DDT. Full article
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12 pages, 849 KiB  
Review
The Role of the Rad55–Rad57 Complex in DNA Repair
by Upasana Roy and Eric C. Greene
Genes 2021, 12(9), 1390; https://doi.org/10.3390/genes12091390 - 8 Sep 2021
Cited by 5 | Viewed by 2331
Abstract
Homologous recombination (HR) is a mechanism conserved from bacteria to humans essential for the accurate repair of DNA double-stranded breaks, and maintenance of genome integrity. In eukaryotes, the key DNA transactions in HR are catalyzed by the Rad51 recombinase, assisted by a host [...] Read more.
Homologous recombination (HR) is a mechanism conserved from bacteria to humans essential for the accurate repair of DNA double-stranded breaks, and maintenance of genome integrity. In eukaryotes, the key DNA transactions in HR are catalyzed by the Rad51 recombinase, assisted by a host of regulatory factors including mediators such as Rad52 and Rad51 paralogs. Rad51 paralogs play a crucial role in regulating proper levels of HR, and mutations in the human counterparts have been associated with diseases such as cancer and Fanconi Anemia. In this review, we focus on the Saccharomyces cerevisiae Rad51 paralog complex Rad55–Rad57, which has served as a model for understanding the conserved role of Rad51 paralogs in higher eukaryotes. Here, we discuss the results from early genetic studies, biochemical assays, and new single-molecule observations that have together contributed to our current understanding of the molecular role of Rad55–Rad57 in HR. Full article
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15 pages, 2353 KiB  
Review
Polymerase θ Coordinates Multiple Intrinsic Enzymatic Activities during DNA Repair
by Karl E. Zahn and Ryan B. Jensen
Genes 2021, 12(9), 1310; https://doi.org/10.3390/genes12091310 - 25 Aug 2021
Cited by 16 | Viewed by 4243
Abstract
The POLQ gene encodes DNA polymerase θ, a 2590 amino acid protein product harboring DNA-dependent ATPase, template-dependent DNA polymerase, dNTP-dependent endonuclease, and 5′–dRP lyase functions. Polymerase θ participates at an essential step of a DNA double-strand break repair pathway able to join 5′-resected [...] Read more.
The POLQ gene encodes DNA polymerase θ, a 2590 amino acid protein product harboring DNA-dependent ATPase, template-dependent DNA polymerase, dNTP-dependent endonuclease, and 5′–dRP lyase functions. Polymerase θ participates at an essential step of a DNA double-strand break repair pathway able to join 5′-resected substrates by locating and pairing microhomologies present in 3′-overhanging single-stranded tails, cleaving the extraneous 3′-DNA by dNTP-dependent end-processing, before extending the nascent 3′ end from the microhomology annealing site. Metazoans require polymerase θ for full resistance to DNA double-strand break inducing agents but can survive knockout of the POLQ gene. Cancer cells with compromised homologous recombination, or other DNA repair defects, over-utilize end-joining by polymerase θ and often over-express the POLQ gene. This dependency points to polymerase θ as an ideal drug target candidate and multiple drug-development programs are now preparing to enter clinical trials with small-molecule inhibitors. Specific inhibitors of polymerase θ would not only be predicted to treat BRCA-mutant cancers, but could thwart accumulated resistance to current standard-of-care cancer therapies and overcome PARP-inhibitor resistance in patients. This article will discuss synthetic lethal strategies targeting polymerase θ in DNA damage-response-deficient cancers and summarize data, describing molecular structures and enzymatic functions. Full article
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