-
Cell Reports Aug 2022A critical determinant of DNA repair pathway choice is REV7, an adaptor that binds to various DNA repair proteins through its C-terminal seatbelt domain. The REV7...
A critical determinant of DNA repair pathway choice is REV7, an adaptor that binds to various DNA repair proteins through its C-terminal seatbelt domain. The REV7 seatbelt binds to either REV3, activating translesion synthesis, or to SHLD3, activating non-homologous end joining (NHEJ) repair. Recent studies have identified another REV7 seatbelt-binding protein, CHAMP1 (chromosome alignment-maintaining phosphoprotein 1), though its possible role in DNA repair is unknown. Here, we show that binding of CHAMP1 to REV7 activates homologous recombination (HR) repair. Mechanistically, CHAMP1 binds directly to REV7 and reduces the level of the Shieldin complex, causing an increase in double-strand break end resection. CHAMP1 also interacts with POGZ in a heterochromatin complex further promoting HR repair. Importantly, in human tumors, CHAMP1 overexpression promotes HR, confers poly (ADP-ribose) polymerase inhibitor resistance, and correlates with poor prognosis. Thus, by binding to either SHLD3 or CHAMP1 through its seatbelt, the REV7 protein can promote either NHEJ or HR repair, respectively.
Topics: Cell Cycle Proteins; Chromosomal Proteins, Non-Histone; DNA End-Joining Repair; DNA Repair; Homologous Recombination; Humans; Mad2 Proteins; Phosphoproteins; Poly(ADP-ribose) Polymerase Inhibitors; Recombinational DNA Repair; Transposases
PubMed: 36044844
DOI: 10.1016/j.celrep.2022.111297 -
Molecular Cell Feb 2015Double-strand breaks (DSBs) threaten chromosome integrity. The most accurate repair of DSBs is by homologous recombination (HR), catalyzed by recombination proteins such... (Review)
Review
Double-strand breaks (DSBs) threaten chromosome integrity. The most accurate repair of DSBs is by homologous recombination (HR), catalyzed by recombination proteins such as Rad51. Three papers in this issue of Molecular Cell (Fasching et al., 2015; Kaur et al., 2015; Tang et al., 2015) now reveal the role of three of these proteins in budding yeast: Sgs1 (BLM homolog), Top3 (TOPIIIα homolog), and Rmi1. They demonstrate several steps where all three proteins act together, and find additional functions of the Top3-Rmi1 subcomplex that are critical for the completion of meiosis.
Topics: Chromosome Segregation; DNA Topoisomerases, Type I; DNA-Binding Proteins; Homologous Recombination; Humans; Meiosis; Models, Genetic; Rad51 Recombinase; RecQ Helicases; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins
PubMed: 25699706
DOI: 10.1016/j.molcel.2015.02.004 -
DNA Repair Sep 2023The perturbation of DNA replication, a phenomena termed "replication stress", is a driving force of genome instability and a hallmark of cancer cells. Among the DNA... (Review)
Review
The perturbation of DNA replication, a phenomena termed "replication stress", is a driving force of genome instability and a hallmark of cancer cells. Among the DNA repair mechanisms that contribute to tolerating replication stress, the homologous recombination pathway is central to the alteration of replication fork progression. In many organisms, defects in the homologous recombination machinery result in increased cell sensitivity to replication-blocking agents and a higher risk of cancer in humans. Moreover, the status of homologous recombination in cancer cells often correlates with the efficacy of anti-cancer treatment. In this review, we discuss our current understanding of the different functions of homologous recombination in fixing replication-associated DNA damage and contributing to complete genome duplication. We also examine which functions are pivotal in preventing cancer and genome instability.
Topics: Humans; DNA Replication; DNA Damage; Homologous Recombination; DNA Repair; Genomic Instability
PubMed: 37541027
DOI: 10.1016/j.dnarep.2023.103548 -
Clinical Cancer Research : An Official... Apr 2022To study associations across tumor types between genome-wide loss of heterozygosity (gLOH) and alterations in homologous recombination repair (HRR)-associated genes...
PURPOSE
To study associations across tumor types between genome-wide loss of heterozygosity (gLOH) and alterations in homologous recombination repair (HRR)-associated genes beyond BRCA1 and BRCA2.
EXPERIMENTAL DESIGN
Genomic profiling using a targeted next-generation sequencing assay examining 324-465 genes (FoundationOne, FoundationOne Heme, and FoundationOne CDx; Foundation Medicine, Inc.) was performed in a cohort of 160,790 samples across different tumor types. Zygosity predictions and gLOH status were calculated and linked with alterations in 18 HRR-associated genes (BRCA1, BRCA2, PALB2, BARD1, ATR, ATRX, ATM, BAP1, RAD51B, RAD51C, RAD51D, BRIP1, NBN, CHEK1, CHEK2, FANCA, FANCC, MRE11) and other genomic features, using Fisher's exact test and Mann-Whitney U tests.
RESULTS
We identified a strong correlation between elevated gLOH and biallelic alterations in a core set of HRR-associated genes beyond BRCA1 and BRCA2, such as BARD1, PALB2, FANCC, RAD51C, and RAD51D (particularly in breast, ovarian, pancreatic, and prostate cancer). Monoallelic/heterozygous alterations in HRR-associated genes were not associated with elevated gLOH. gLOH was also independently associated with TP53 loss. Co-occurrence of TP53 loss and alterations in HRR-associated genes, and combined loss of TP53-PTEN or TP53-RB1, was associated with a higher gLOH than each of the events separately.
CONCLUSIONS
Biallelic alterations in core HRR-associated genes are frequent, strongly associated with elevated gLOH, and enriched in breast, ovarian, pancreatic, and prostate cancer. This analysis could inform the design of the next generation of clinical trials examining DNA repair-targeting agents, including PARP inhibitors.
Topics: Breast Neoplasms; DNA Repair; Genetic Predisposition to Disease; Heterozygote; Homologous Recombination; Humans; Male; Poly(ADP-ribose) Polymerase Inhibitors; Prostatic Neoplasms; Recombinational DNA Repair
PubMed: 34740923
DOI: 10.1158/1078-0432.CCR-21-2096 -
Current Opinion in Genetics &... Dec 2021Exposure to environmental mutagens but also cell-endogenous processes can create DNA double-strand breaks (DSBs) in a cell's genome. DSBs need to be repaired accurately... (Review)
Review
Exposure to environmental mutagens but also cell-endogenous processes can create DNA double-strand breaks (DSBs) in a cell's genome. DSBs need to be repaired accurately and timely to ensure genomic integrity and cell survival. One major DSB repair mechanism, called homologous recombination, relies on the nucleolytic degradation of the 5'-terminated strands in a process termed end resection. Here, we review new insights into end resection with a focus on the mechanistic interplay of the nucleases, helicases, and accessory factors involved.
Topics: DNA; DNA Breaks, Double-Stranded; DNA Helicases; DNA Repair; Homologous Recombination
PubMed: 34329854
DOI: 10.1016/j.gde.2021.07.004 -
International Journal of Molecular... Jun 2022The role of genetic exchanges, i.e., homologous recombination (HR) and horizontal gene transfer (HGT), in bacteria cannot be overestimated for it is a pivotal mechanism... (Review)
Review
The role of genetic exchanges, i.e., homologous recombination (HR) and horizontal gene transfer (HGT), in bacteria cannot be overestimated for it is a pivotal mechanism leading to their evolution and adaptation, thus, tracking the signs of recombination and HGT events is importance both for fundamental and applied science. To date, dozens of bioinformatics tools for revealing recombination signals are available, however, their pros and cons as well as the spectra of solvable tasks have not yet been systematically reviewed. Moreover, there are two major groups of software. One aims to infer evidence of HR, while the other only deals with horizontal gene transfer (HGT). However, despite seemingly different goals, all the methods use similar algorithmic approaches, and the processes are interconnected in terms of genomic evolution influencing each other. In this review, we propose a classification of novel instruments for both HR and HGT detection based on the genomic consequences of recombination. In this context, we summarize available methodologies paying particular attention to the type of traceable events for which a certain program has been designed.
Topics: Bacteria; Computational Biology; Evolution, Molecular; Gene Transfer, Horizontal; Homologous Recombination; Phylogeny
PubMed: 35682936
DOI: 10.3390/ijms23116257 -
Molecular Cancer Therapeutics Sep 2021Ovarian cancer is the second most common gynecologic malignancy in the United States and the most common cause of gynecologic cancer-related death. The majority of... (Review)
Review
Ovarian cancer is the second most common gynecologic malignancy in the United States and the most common cause of gynecologic cancer-related death. The majority of ovarian cancers ultimately recur despite excellent response rates to upfront platinum- and taxane-based chemotherapy. Maintenance therapy after frontline treatment has emerged in recent years as an effective tool for extending the platinum-free interval of these patients. Maintenance therapy with PARP inhibitors (PARPis), in particular, has become part of standard of care in the upfront setting and in patients with platinum-sensitive disease. Homologous recombination deficient (HRD) tumors have a nonfunctioning homologous recombination repair (HRR) pathway and respond well to PARPis, which takes advantage of synthetic lethality by concomitantly impairing DNA repair mechanisms. Conversely, patients with a functioning HRR pathway, that is, HR-proficient tumors, can still elicit benefit from PARPi, but the efficacy is not as remarkable as what is seen in HRD tumors. PARPis are ineffective in some patients due to HR proficiency, which is either inherent to the tumor or potentially acquired as a method of therapeutic resistance. This review seeks to outline current strategies employed by clinicians and scientists to overcome PARPi resistance-either acquired or inherent to the tumor.
Topics: Animals; Drug Resistance, Neoplasm; Homologous Recombination; Humans; Neoplasms; Poly(ADP-ribose) Polymerase Inhibitors; Recombinational DNA Repair
PubMed: 34172532
DOI: 10.1158/1535-7163.MCT-20-0992 -
Cold Spring Harbor Perspectives in... Mar 2015Homologous recombination (HR) and mismatch repair (MMR) are inextricably linked. HR pairs homologous chromosomes before meiosis I and is ultimately responsible for... (Review)
Review
Homologous recombination (HR) and mismatch repair (MMR) are inextricably linked. HR pairs homologous chromosomes before meiosis I and is ultimately responsible for generating genetic diversity during sexual reproduction. HR is initiated in meiosis by numerous programmed DNA double-strand breaks (DSBs; several hundred in mammals). A characteristic feature of HR is the exchange of DNA strands, which results in the formation of heteroduplex DNA. Mismatched nucleotides arise in heteroduplex DNA because the participating parental chromosomes contain nonidentical sequences. These mismatched nucleotides may be processed by MMR, resulting in nonreciprocal exchange of genetic information (gene conversion). MMR and HR also play prominent roles in mitotic cells during genome duplication; MMR rectifies polymerase misincorporation errors, whereas HR contributes to replication fork maintenance, as well as the repair of spontaneous DSBs and genotoxic lesions that affect both DNA strands. MMR suppresses HR when the heteroduplex DNA contains excessive mismatched nucleotides, termed homeologous recombination. The regulation of homeologous recombination by MMR ensures the accuracy of DSB repair and significantly contributes to species barriers during sexual reproduction. This review discusses the history, genetics, biochemistry, biophysics, and the current state of studies on the role of MMR in homologous and homeologous recombination from bacteria to humans.
Topics: Animals; Biological Evolution; DNA Breaks, Double-Stranded; DNA Mismatch Repair; Homologous Recombination; Humans; Meiosis; Models, Biological; Species Specificity
PubMed: 25731766
DOI: 10.1101/cshperspect.a022657 -
Research in Microbiology 2022In the past decades, the ability of Giardia duodenalis to perform homologous recombination has been suggested, supported by the observations of genomic integration of...
In the past decades, the ability of Giardia duodenalis to perform homologous recombination has been suggested, supported by the observations of genomic integration of foreign plasmids and the disruption of genes using CRISPR technology. Unfortunately, the direct study of a HR mechanism has not been addressed, which would be pertinent in a minimalist organism lacking fundamental DNA-repair elements and even complete pathways. In addition, the constant ploidy changes through the life cycle of this parasite highlight the conservation and relevance of homologous recombination in maintaining genomic stability. In this research, we analyzed different recombinable plasmid systems and their outcomes after G. duodenalis transfection, using this approach we determined genomic, intra-plasmid and inter-plasmid recombination, moreover, we examined the presence of the non-conservative single-strand annealing pathway. With the intention of corroborating that the observed processes were done by homologous recombination, we used a chemical inhibitor named Mirin, which specifically inhibits Mre11 3'- 5' exonuclease activity, one of the first steps involved in homologous recombination and fundamental to success in repairing. Overall, these results describe the multiple recombinational substrates used by G. duodenalis to achieve HR and demonstrate the presence and use of single-strand annealing recombination.
Topics: Giardia lamblia; Homologous Recombination; DNA Repair; Clustered Regularly Interspaced Short Palindromic Repeats; Genomics
PubMed: 35944795
DOI: 10.1016/j.resmic.2022.103984 -
Molecular Microbiology May 2019Double-strand breaks (DSBs) are the most detrimental DNA damage encountered by bacterial cells. DBSs can be repaired by homologous recombination thanks to the... (Review)
Review
Double-strand breaks (DSBs) are the most detrimental DNA damage encountered by bacterial cells. DBSs can be repaired by homologous recombination thanks to the availability of an intact DNA template or by Non-Homologous End Joining (NHEJ) when no intact template is available. Bacterial NHEJ is performed by sets of proteins of growing complexity from Bacillus subtilis and Mycobacterium tuberculosis to Streptomyces and Sinorhizobium meliloti. Here, we discuss the contribution of these models to the understanding of the bacterial NHEJ repair mechanism as well as the involvement of NHEJ partners in other DNA repair pathways. The importance of NHEJ and of its complexity is discussed in the perspective of regulation through the biological cycle of the bacteria and in response to environmental stimuli. Finally, we consider the role of NHEJ in genome evolution, notably in horizontal gene transfer.
Topics: Bacteria; DNA Breaks, Double-Stranded; DNA End-Joining Repair; Gene Expression Regulation, Bacterial; Gene Transfer, Horizontal; Genome, Bacterial; Homologous Recombination
PubMed: 30746801
DOI: 10.1111/mmi.14218