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Mechanism of tandem duplication formation in BRCA1 -mutant cells

Published on Nov 1, 2017in Nature43.07
· DOI :10.1038/nature24477
Nicholas A. Willis12
Estimated H-index: 12
(Harvard University),
Richard L. Frock14
Estimated H-index: 14
(HHMI: Howard Hughes Medical Institute)
+ 7 AuthorsRalph Scully38
Estimated H-index: 38
(Harvard University)
Abstract
BRCA1, but not BRCA2, suppresses the formation of tandem duplications at stalled replication forks in primary mammalian cells.
  • References (53)
  • Citations (21)
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References53
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#1Weixing ZhaoH-Index: 18
Last. Patrick SungH-Index: 76
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The tumour suppressor complex BRCA1–BARD1, which facilitates the generation of a single-stranded DNA template during homologous recombination, also binds to the recombinase RAD51 and enhances its function.
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#1Helen Davies (Wellcome Trust Sanger Institute)H-Index: 46
#2Dominik Glodzik (Wellcome Trust Sanger Institute)H-Index: 9
Last. Serena Nik-Zainal (Cambridge University Hospitals NHS Foundation Trust)H-Index: 39
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Approximately 1-5% of breast cancers are attributed to inherited mutations in BRCA1 or BRCA2 and are selectively sensitive to poly(ADP-ribose) polymerase (PARP) inhibitors. In other cancer types, germline and/or somatic mutations in BRCA1 and/or BRCA2 (BRCA1/BRCA2) also confer selective sensitivity to PARP inhibitors. Thus, assays to detect BRCA1/BRCA2-deficient tumors have been sought. Recently, somatic substitution, insertion/deletion and rearrangement patterns, or 'mutational signatures', wer...
149 CitationsSource
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Summary Homologous recombination (HR) is necessary to counteract DNA replication stress. Common fragile site (CFS) loci are particularly sensitive to replication stress and undergo pathological rearrangements in tumors. At these loci, replication stress frequently activates DNA repair synthesis in mitosis. This mitotic DNA synthesis, termed MiDAS, requires the MUS81-EME1 endonuclease and a non-catalytic subunit of the Pol-delta complex, POLD3. Here, we examine the contribution of HR factors in p...
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#1Andrea J. Hartlerode (BIDMC: Beth Israel Deaconess Medical Center)H-Index: 7
#2Nicholas A. Willis (BIDMC: Beth Israel Deaconess Medical Center)H-Index: 12
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A proportion of homologous recombination (HR) events in mammalian cells resolve by “long tract” gene conversion, reflecting copying of several kilobases from the donor sister chromatid prior to termination. Cells lacking the major hereditary breast/ovarian cancer predisposition genes, BRCA1 or BRCA2, or certain other HR-defective cells, reveal a bias in favor of long tract gene conversion, suggesting that this aberrant HR outcome might be connected with genomic instability. If termination of gen...
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Menghi et al. (1) report a metric to classify tumors into those with and without a tandem duplicator phenotype (TDP), using the frequency of tandem duplications (TDs) in 277 whole-genome sequenced samples. Building on a previous method (2), Menghi et al. (1) identified TDs from SNP array data, and found that the TDP was strongly associated with response to the DNA damaging chemotherapeutic, cisplatin. These findings supplement the growing recognition that genome-wide signatures of mutator phenot...
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Watkins et al. (1) note that tandem duplications (TDs) are a feature of two distinct cancer phenotypes, distinguished based on TD span size (1 Kb–2 Mb vs. 2–10 Mb) and breast cancer 1 ( BRCA1 ) status (inactivation vs. wild-type), present at different frequencies in triple-negative breast cancer (TNBC). The authors suggest that our recent study (2) only captures the first type of TD phenotype (TDP), and that the second form of TDP may have implications in the assessment of genomic instability-ba...
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Encounters and conflicts between the transcription and replication machineries are common and represent a major intrinsic source of genome instability. Recent data shed new light on the biological relevance of transcription–replication conflicts and the factors and mechanisms involved in either preventing or resolving them.
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We analysed whole-genome sequences of 560 breast cancers to advance understanding of the driver mutations conferring clonal advantage and the mutational processes generating somatic mutations. We found that 93 protein-coding cancer genes carried probable driver mutations. Some non-coding regions exhibited high mutation frequencies, but most have distinctive structural features probably causing elevated mutation rates and do not contain driver mutations. Mutational signature analysis was extended...
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This protocol describes a genome-wide method to detect and to quantify DNA double-stranded breaks (DSBs). The approach is applicable to endogenous DSBs, but it can also be used to characterize the activity of engineered nucleases, including Cas9.
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Next-generation sequencing studies have revealed genome-wide structural variation patterns in cancer, such as chromothripsis and chromoplexy, that do not engage a single discernable driver mutation, and whose clinical relevance is unclear. We devised a robust genomic metric able to identify cancers with a chromotype called tandem duplicator phenotype (TDP) characterized by frequent and distributed tandem duplications (TDs). Enriched only in triple-negative breast cancer (TNBC) and in ovarian, en...
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BRCA1/2 help maintain genomic integrity by stabilizing stalled forks. Here, we identify the E3 ligase RFWD3 as an essential modulator of stalled fork stability in BRCA2-deficient cells and show that codepletion of RFWD3 rescues fork degradation, collapse, and cell sensitivity upon replication stress. Stalled forks in BRCA2-deficient cells accumulate phosphorylated and ubiquitinated replication protein A (ubq-pRPA), the latter of which is mediated by RFWD3. Generation of this intermediate require...
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