BRCA2 Is Required for Homology-Directed Repair of Chromosomal Breaks

Moynahan, Mary Ellen; Pierce, Andrew J.; Jasin, Maria

doi:10.1016/s1097-2765(01)00174-5

Cited by 883 publications

(735 citation statements)

References 57 publications

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“…Interestingly, the formation of RAD51 foci after DNA damage was shown to be dependent upon functional BRCA2, a result that led to suggestions that BRCA2 is required for the recruitment of RAD51 to sites of DSBs, and thus for the cellular function of RAD51 (Sharan et al, 1997;Yuan et al, 1999). Consistent with this view, BRCA2-deficient murine and human cells exhibit a spontaneous genome instability phenotype that involves the accumulation of chromosome breaks and radial chromosomes, presumably due to defects in the repair of replicationassociated DSBs (Patel et al, 1998;Yu et al, 2000;Moynahan et al, 2001;Tutt et al, 2001).…”

Section: Regulation Of Recombination By Brca2mentioning

confidence: 90%

“…The RAD51 nucleoprotein filament mediates a search for homology within the sister chromatid, which in turn serves as a template for DNA synthesis to restore any lost sequences at the break site and ultimately regenerate intact DNA (West, 2003;Sung and Klein, 2006). The tumour suppressor and breast cancer-susceptibility gene BRCA2 is required for normal levels of HR-mediated DSB repair (Yu et al, 2000;Moynahan et al, 2001), providing an important link between the ability of a cell to maintain genome stability and tumorigenesis.…”

Section: The Dual Functions Of Recombinationmentioning

confidence: 99%

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BRCA2: a universal recombinase regulator

2007

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Homologous recombination has a dual role in eukaryotic organisms. Firstly, it is responsible for the creation of genetic variability during meiosis by directing the formation of reciprocal crossovers that result in random combinations of alleles and traits. Secondly, in mitotic cells, it maintains the integrity of the genome by promoting the faithful repair of DNA double-strand breaks (DSBs). In vertebrates, it therefore plays a key role in tumour avoidance. Mutations in the tumour suppressor protein BRCA2 are associated with predisposition to breast and ovarian cancers, and loss of BRCA2 function leads to genetic instability. BRCA2 protein interacts directly with the RAD51 recombinase and regulates recombinationmediated DSB repair, accounting for the high levels of spontaneous chromosomal aberrations seen in BRCA2-defective cells. Recent observations indicate that BRCA2 also plays a critical role in meiotic recombination, this time through direct interactions with the meiosis-specific recombinase DMC1. The interactions of BRCA2 with RAD51 and DMC1 lead us to suggest that the BRCA2 tumour suppressor is a universal regulator of recombinase actions.

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Section: Regulation Of Recombination By Brca2mentioning

confidence: 90%

Section: The Dual Functions Of Recombinationmentioning

confidence: 99%

BRCA2: a universal recombinase regulator

2007

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“…Direct evidence of a role for BRCA1 and BRCA2 in HR came from quantifying recombinational repair of a site-specific DSB in BRCA mutant cell lines. Either BRCA1 or BRCA2 mutation reduces the efficiency of HR induced by a site-specific DSB [83][84][85][86][87]. Errorprone repair of the DSB by single strand annealing (SSA) is increased in BRCA2 mutants [87,88]-a pattern reminiscent of HR mutants in yeast and in other vertebrate cells.…”

Section: Role Of Brca1 and Brca2 In Hr Regulationmentioning

confidence: 99%

Minding the gap: The underground functions of BRCA1 and BRCA2 at stalled replication forks

Nagaraju

Scully

2007

DNA Repair

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The hereditary breast and ovarian cancer predisposition genes, BRCA1 and BRCA2, participate in the repair of DNA double strand breaks by homologous recombination. Circumstantial evidence implicates these genes in recombinational responses to DNA polymerase stalling during the S phase of the cell cycle. These responses play a key role in preventing genomic instability and cancer. Here, we review the current literature implicating the BRCA pathway in HR at stalled replication forks and explore the hypothesis that BRCA1 and BRCA2 participate in the recombinational resolution of single stranded DNA lesions termed "daughter strand gaps", generated during replication across a damaged DNA template.

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“…Extensive studies have indicated that BRCA2 has an important function in DNA repair (Connor et al, 1997;Mizuta et al, 1997;Sharan et al, 1997;Wong et al, 1997;Chen et al, 1998;Patel et al, 1998). Recent reports indicate that BRCA2 acts in the homology-directed recombinational repair of double-strand DNA breaks (Davies et al, 2001;Moynahan et al, 2001;Xia et al, 2001;Kraakman-van der Zwet et al, 2002). The finding that BRCA2 is mutated in Faconi anemia patients further indicates that BRCA2 functions in a DNA damage-repair pathway (Howlett et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

DSS1 is required for the stability of BRCA2

et al. 2005

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DSS1 is an evolutionarily conserved acidic protein that binds to BRCA2. However, study of the function of DSS1 in mammalian cells has been hampered because endogenous DSS1 has not been detectable by Western blotting. Here, we developed a modified Western blotting protocol that detects endogenous DSS1 protein, and used it to study the function of DSS1 and its interaction with BRCA2 in mammalian cells. We found that essentially all BRCA2 in human cell lines is associated with DSS1. Importantly, we found that RNAi knockdown of DSS1 in human cell lines led to dramatic loss of BRCA2 protein, mainly due to its increased degradation. Furthermore, the stability of BRCA2 mutant devoid of the DSS1-binding domain is unaffected by the depletion of DSS1. Most notably, like BRCA2 depletion, DSS1 depletion also led to hypersensitivity to DNA damage. These results demonstrated that the stability of BRCA2 protein in mammalian cells depends on the presence of DSS1. Deletion or mutation of DSS1 or suppression of its expression by other mechanisms are therefore potential causative mechanisms for human breast and ovarian cancer. Such mechanisms may be relevant to sporadic as well as familiar breast cancer where BRCA1 and BRCA2 mutations are not present.

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BRCA2 Is Required for Homology-Directed Repair of Chromosomal Breaks

Cited by 883 publications

References 57 publications

BRCA2: a universal recombinase regulator

BRCA2: a universal recombinase regulator

Minding the gap: The underground functions of BRCA1 and BRCA2 at stalled replication forks

DSS1 is required for the stability of BRCA2

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