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The Journal of Biological Chemistry Jul 2018Homologous recombination enables the cell to access and copy intact DNA sequence information in , particularly to repair DNA damage affecting both strands of the double... (Review)
Review
Homologous recombination enables the cell to access and copy intact DNA sequence information in , particularly to repair DNA damage affecting both strands of the double helix. Here, we discuss the DNA transactions and enzymatic activities required for this elegantly orchestrated process in the context of the repair of DNA double-strand breaks in somatic cells. This includes homology search, DNA strand invasion, repair DNA synthesis, and restoration of intact chromosomes. Aspects of DNA topology affecting individual steps are highlighted. Overall, recombination is a dynamic pathway with multiple metastable and reversible intermediates designed to achieve DNA repair with high fidelity.
Topics: Animals; DNA Breaks, Double-Stranded; DNA Repair; DNA Replication; Homologous Recombination; Humans; Signal Transduction
PubMed: 29599286
DOI: 10.1074/jbc.TM118.000372 -
International Journal of Molecular... Dec 2021Homologous recombination (HR) is a vital process for repairing DNA double-strand breaks. Germline variants in the HR pathway, comprising at least 10 genes, such as , , ,... (Review)
Review
Homologous recombination (HR) is a vital process for repairing DNA double-strand breaks. Germline variants in the HR pathway, comprising at least 10 genes, such as , , , , , , (), , , and , lead to inherited susceptibility to specific types of cancers, including those of the breast, ovaries, prostate, and pancreas. The penetrance of germline pathogenic variants of each gene varies, whereas all their associated protein products are indispensable for maintaining a high-fidelity DNA repair system by HR. The present review summarizes the basic molecular mechanisms and components that collectively play a role in maintaining genomic integrity against DNA double-strand damage and their clinical implications on each type of hereditary tumor.
Topics: Genetic Predisposition to Disease; Genetic Testing; Germ-Line Mutation; Homologous Recombination; Humans; Neoplasms; Precision Medicine
PubMed: 35008774
DOI: 10.3390/ijms23010348 -
Journal of Hepatology Feb 2023The heritability and actionability of variants in homologous recombination-related genes in biliary tract cancers (BTCs) are uncertain. Although associations between BTC...
BACKGROUND & AIMS
The heritability and actionability of variants in homologous recombination-related genes in biliary tract cancers (BTCs) are uncertain. Although associations between BTC and BRCA germline variants have been reported, homologous recombination deficiency has not been investigated in BTCs.
METHODS
We sequenced germline variants in 27 cancer-predisposing genes in 1,292 BTC cases and 37,583 controls without a personal nor family history of cancer. We compared pathogenic germline variant frequencies between cases and controls and documented the demographic and clinical characteristics of carriers. In addition, whole-genome sequencing of 45 BTC tissues was performed to evaluate homologous recombination deficiency status.
RESULTS
Targeted sequencing identified 5,018 germline variants, which were classified into 317 pathogenic, 3,611 variants of uncertain significance, and 1,090 benign variants. Seventy-one BTC cases (5.5%) had at least one pathogenic variant among 27 cancer-predisposing genes. Pathogenic germline variants enriched in BTCs were present in BRCA1, BRCA2, APC, and MSH6 (p <0.00185). PALB2 variants were marginally associated with BTC (p = 0.01). APC variants were predominantly found in ampulla of Vater carcinomas. Whole-genome sequencing demonstrated that three BTCs with pathogenic germline variants in BRCA2 and PALB2, accompanied by loss of heterozygosity, displayed homologous recombination deficiency. Conversely, pathogenic germline variants without a second hit or variants of other homologous recombination-related genes such as ATM and BRIP1 showed homologous recombination-proficient phenotypes.
CONCLUSIONS
In this study, we describe the heritability and actionability of variants in homologous recombination-related genes, which could be used to guide screening and therapeutic strategies for BTCs.
IMPACT AND IMPLICATIONS
We found that 5.5% of biliary tract cancers (BTCs) in a Japanese population possessed hereditary cancer-predisposing gene alterations, including in BRCA and genes associated with colorectal cancer. Two hits in homologous recombination-related genes were required to confer a homologous recombination-deficient phenotype. PARP inhibitors and DNA-damaging regimens may be effective strategies against BTCs exhibiting homologous recombination deficiency. Hence, in this study, genome-wide sequencing has revealed a potential new therapeutic strategy that could be applied to a subset of BTCs.
Topics: Humans; Genetic Predisposition to Disease; Germ-Line Mutation; Biliary Tract Neoplasms; Whole Genome Sequencing; Homologous Recombination
PubMed: 36243179
DOI: 10.1016/j.jhep.2022.09.025 -
Nature Jun 2022Chromosomal instability (CIN) results in the accumulation of large-scale losses, gains and rearrangements of DNA. The broad genomic complexity caused by CIN is a...
Chromosomal instability (CIN) results in the accumulation of large-scale losses, gains and rearrangements of DNA. The broad genomic complexity caused by CIN is a hallmark of cancer; however, there is no systematic framework to measure different types of CIN and their effect on clinical phenotypes pan-cancer. Here we evaluate the extent, diversity and origin of CIN across 7,880 tumours representing 33 cancer types. We present a compendium of 17 copy number signatures that characterize specific types of CIN, with putative aetiologies supported by multiple independent data sources. The signatures predict drug response and identify new drug targets. Our framework refines the understanding of impaired homologous recombination, which is one of the most therapeutically targetable types of CIN. Our results illuminate a fundamental structure underlying genomic complexity in human cancers and provide a resource to guide future CIN research.
Topics: Chromosomal Instability; Homologous Recombination; Humans; Molecular Targeted Therapy; Neoplasms
PubMed: 35705807
DOI: 10.1038/s41586-022-04789-9 -
Annual Review of Genetics Nov 2020Accurate DNA repair and replication are critical for genomic stability and cancer prevention. and its gene family are key regulators of DNA fidelity through diverse... (Review)
Review
Accurate DNA repair and replication are critical for genomic stability and cancer prevention. and its gene family are key regulators of DNA fidelity through diverse roles in double-strand break repair, replication stress, and meiosis. RAD51 is an ATPase that forms a nucleoprotein filament on single-stranded DNA. RAD51 has the function of finding and invading homologous DNA sequences to enable accurate and timely DNA repair. Its paralogs, which arose from ancient gene duplications of , have evolved to regulate and promote RAD51 function. Underscoring its importance, misregulation of RAD51, and its paralogs, is associated with diseases such as cancer and Fanconi anemia. In this review, we focus on the mammalian RAD51 structure and function and highlight the use of model systems to enable mechanistic understanding of RAD51 cellular roles. We also discuss how misregulation of the gene family members contributes to disease and consider new approaches to pharmacologically inhibit RAD51.
Topics: Animals; DNA; DNA Repair; Genomic Instability; Homologous Recombination; Humans; Rad51 Recombinase
PubMed: 32663049
DOI: 10.1146/annurev-genet-021920-092410 -
Nature Cancer Jun 2021DNA polymerase theta (POLθ) is synthetic lethal with Homologous Recombination (HR) deficiency and thus a candidate target for HR-deficient cancers. Through...
DNA polymerase theta (POLθ) is synthetic lethal with Homologous Recombination (HR) deficiency and thus a candidate target for HR-deficient cancers. Through high-throughput small molecule screens we identified the antibiotic Novobiocin (NVB) as a specific POLθ inhibitor that selectively kills HR-deficient tumor cells and . NVB directly binds to the POLθ ATPase domain, inhibits its ATPase activity, and phenocopies POLθ depletion. NVB kills HR-deficient breast and ovarian tumors in GEMM, xenograft and PDX models. Increased POLθ levels predict NVB sensitivity, and BRCA-deficient tumor cells with acquired resistance to PARP inhibitors (PARPi) are sensitive to NVB and Mechanistically, NVB-mediated cell death in PARPi-resistant cells arises from increased double-strand break end resection, leading to accumulation of single-strand DNA intermediates and non-functional RAD51 foci. Our results demonstrate that NVB may be useful alone or in combination with PARPi in treating HR-deficient tumors, including those with acquired PARPi resistance. (151/150).
Topics: Adenosine Triphosphatases; Female; Homologous Recombination; Humans; Ovarian Neoplasms; Poly(ADP-ribose) Polymerase Inhibitors
PubMed: 34179826
DOI: 10.1038/s43018-021-00203-x -
The Oncologist Mar 2022Homologous recombination deficiency (HRD) is a phenotype that is characterized by the inability of a cell to effectively repair DNA double-strand breaks using the...
BACKGROUND
Homologous recombination deficiency (HRD) is a phenotype that is characterized by the inability of a cell to effectively repair DNA double-strand breaks using the homologous recombination repair (HRR) pathway. Loss-of-function genes involved in this pathway can sensitize tumors to poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitors and platinum-based chemotherapy, which target the destruction of cancer cells by working in concert with HRD through synthetic lethality. However, to identify patients with these tumors, it is vital to understand how to best measure homologous repair (HR) status and to characterize the level of alignment in these measurements across different diagnostic platforms. A key current challenge is that there is no standardized method to define, measure, and report HR status using diagnostics in the clinical setting.
METHODS
Friends of Cancer Research convened a consortium of project partners from key healthcare sectors to address concerns about the lack of consistency in the way HRD is defined and methods for measuring HR status.
RESULTS
This publication provides findings from the group's discussions that identified opportunities to align the definition of HRD and the parameters that contribute to the determination of HR status. The consortium proposed recommendations and best practices to benefit the broader cancer community.
CONCLUSION
Overall, this publication provides additional perspectives for scientist, physician, laboratory, and patient communities to contextualize the definition of HRD and various platforms that are used to measure HRD in tumors.
Topics: BRCA1 Protein; DNA Repair; Female; Homologous Recombination; Humans; Ovarian Neoplasms; Poly(ADP-ribose) Polymerase Inhibitors; Poly(ADP-ribose) Polymerases; Recombinational DNA Repair
PubMed: 35274707
DOI: 10.1093/oncolo/oyab053 -
Modern Pathology : An Official Journal... Mar 2023The repair of DNA double-stranded breaks relies on the homologous recombination repair pathway and is critical to cell function. However, this pathway can be lost in... (Review)
Review
The repair of DNA double-stranded breaks relies on the homologous recombination repair pathway and is critical to cell function. However, this pathway can be lost in some cancers such as breast, ovarian, endometrial, pancreatic, and prostate cancers. Cancer cells with homologous recombination deficiency (HRD) are sensitive to targeted inhibition of poly-ADP ribose polymerase (PARP), a key component of alternative backup DNA repair pathways. Identifying patients with cancer with HRD biomarkers allows the identification of patients likely to benefit from PARP inhibitor therapies. In this study, we describe the causes of HRD, the underlying molecular changes resulting from HRD that form the basis of different molecular HRD assays, and discuss the issues around their clinical use. This overview is directed toward practicing pathologists wishing to be informed of this new predictive biomarker, as PARP inhibitors are increasingly used in standard care settings.
Topics: Female; Humans; Recombinational DNA Repair; Ovarian Neoplasms; Homologous Recombination; Pathologists; DNA Repair
PubMed: 36788098
DOI: 10.1016/j.modpat.2022.100049 -
Molecular Cell Jul 2022The efficiency of homologous recombination (HR) in the repair of DNA double-strand breaks (DSBs) is closely associated with genome stability and tumor response to...
The efficiency of homologous recombination (HR) in the repair of DNA double-strand breaks (DSBs) is closely associated with genome stability and tumor response to chemotherapy. While many factors have been functionally characterized in HR, such as TOPBP1, their precise regulation remains unclear. Here, we report that TOPBP1 interacts with the RNA-binding protein HTATSF1 in a cell-cycle- and phosphorylation-dependent manner. Mechanistically, CK2 phosphorylates HTATSF1 to facilitate binding to TOPBP1, which promotes S-phase-specific TOPBP1 recruitment to damaged chromatin and subsequent RPA/RAD51-dependent HR, genome integrity, and cancer-cell viability. The localization of HTATSF1-TOPBP1 to DSBs is potentially independent of the transcription-coupled RNA-binding and processing capacity of HTATSF1 but rather relies on the recognition of poly(ADP-ribosyl)ated RPA by HTATSF1, which can be blunted with PARP inhibitors. Together, our study provides a mechanistic insight into TOPBP1 loading at HR-prone DSB sites via HTATSF1 and reveals how RPA-RAD51 exchange is tuned by a PARylation-phosphorylation cascade.
Topics: DNA Breaks, Double-Stranded; DNA Repair; Homologous Recombination; Phosphorylation; Poly ADP Ribosylation; Rad51 Recombinase
PubMed: 35597237
DOI: 10.1016/j.molcel.2022.04.031 -
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