Involvement of Brca2 in DNA Repair

Patel, Ketan; Yu, Veronica; Lee, Hyun‐Sook; Corcoran, Anne E.; Thistlethwaite, Fiona; Evans, Martin; Colledge, William H.; Friedman, Lori S.; Ponder, Bruce A.J.; Venkitaraman, Ashok R.

doi:10.1016/s1097-2765(00)80035-0

Cited by 566 publications

(460 citation statements)

References 57 publications

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“…Only a single other codon 212 mutation is represented on the IARC database, this being TTT4TCT in a skin tumour. The recent demonstration that mouse ®broblasts with truncated BRCA2 are more sensitive to UV irradiation than controls (perhaps due to defective nucleotide or base excision repair) is clearly of interest in the context of this observation (Patel et al, 1998). Previous studies of sporadic breast cancer have revealed three codons at which mutation most commonly occurs: 175, 248 and 273 (Levine et al, 1994;Hollstein et al, 1994).…”

Section: Discussionmentioning

confidence: 99%

“…Tumorigenesis in carriers of germ-line mutations in BRCA1 and BRCA2 is invariably accompanied by loss of the wild-type allele (Smith et al, 1992;Neuhausen and Marshall, 1994;Collins et al, 1995;Gudmundsson et al, 1995;Kelsell et al, 1996) suggesting that the proteins encoded by the two genes operate as tumour suppressors. An increasing-body of evidence favours a role for both BRCA1 and BRCA2 in cellular response to DNA damage (Connor et al, 1997;Scully et al, 1997;Patel et al, 1998). It is postulated that the BRCA genes act as caretakers, functioning to maintain genomic stability, rather than as gatekeepers which regulate cellular proliferation (Brugarolas and Jacks, 1997;Kinzler and Vogelstein, 1997).…”

Section: Introductionmentioning

confidence: 99%

“…Analysis of ®broblasts derived from mice homozygous for a truncating mutation in BRCA2 has revealed a proliferation defect associated with p53-dependent induction of p21 Waf1 expression, and a DNA repair defect (Connor et al, 1997). In another study, mouse embryo ®broblasts carrying BRCA2 truncations, were shown to be signi®cantly more sensitive to UV irradiation and the alkylating agent methylmethanesulphonate than wild-type controls, leading to the suggestion that BRCA2 may be associated with a nucleotide excision repair pathway (Patel et al, 1998). However, it is not known whether these defects occur in tumours arising in carriers of germline mutant alleles of BRCA1 and BRCA 2.…”

Section: Introductionmentioning

confidence: 99%

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p53 mutation with frequent novel codons but not a mutator phenotype in BRCA1- and BRCA2-associated breast tumours

et al. 1998

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The status of p53 was investigated in breast tumours arising in germ-line carriers of mutant alleles of BRCA1 and BRCA2 and in a control series of sporadic breast tumours. p53 expression was detected in 20/26 (77%) BRCA1-, 10/22 (45%) BRCA2-associated and 25/72 (35%) grade-matched sporadic tumours. Analysis of p53 sequence revealed that the gene was mutant in 33/50 (66%) BRCA-associated tumours, whereas 7/20 (35%) sporadic grade-matched tumours contained p53 mutation (P50.05). A number of the mutations detected in the BRCA-associated tumours have not been previously described in human cancer databases, whilst others occur extremely rarely. Analysis of additional genes, p16 INK4 , Ki-ras and b-globin revealed absence or very low incidence of mutations, suggesting that the higher frequency of p53 mutation in the BRCA-associated tumours does not re¯ect a generalized increase in susceptibility to the acquisition of somatic mutation. Furthermore, absence of frameshift mutations in the polypurine tracts present in the coding sequence of the TGF b type II receptor (TGF b IIR) and Bax implies that loss of function of BRCA1 or BRCA2 does not confer a mutator phenotype such as that found in tumours with microsatellite instability (MSI). p21 Waf1 was expressed in BRCA-associated tumours regardless of p53 status and, furthermore, some tumours expressing wild-type p53 did not express detectable p21 Waf1 . These data do not support, therefore, the simple model based on studies of BRCA7/7 embryos, in which mutation of p53 in BRCA-associated tumours results in loss of p21 Waf1 expression and deregulated proliferation. Rather, they imply that proliferation of such tumours will be subject to multiple mechanisms of growth regulation.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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p53 mutation with frequent novel codons but not a mutator phenotype in BRCA1- and BRCA2-associated breast tumours

et al. 1998

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“…Germline mutations in the breast-cancer susceptibility gene BRCA2 confer susceptibility to familial early-onset breast and ovarian cancers (Wooster et al, 1994(Wooster et al, , 1995Tavtigian et al, 1996;Brody and Biesecker, 1998;Rahman and Stratton, 1998). 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).…”

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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“…Recent studies also suggest that this complex may function in the cellular response to DNA damage (Connor et al, 1997a;Scully et al, 1997a,b;Patel et al, 1998). As noted above, the primary sequences of BRCA1, BARD1 and BRCA2 are poorly conserved in mammals (mouse/human identities of *57%, 70% and 58%, respectively) and orthologs of these polypeptides are conspicuously absent from at least one lower eukaryote: the budding yeast S. cerevisiae.…”

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confidence: 98%

Conservation of function and primary structure in the BRCA1-associated RING domain (BARD1) protein

et al. 1998

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The BRCA1 gene encodes a tumor suppressor that has been implicated in hereditary forms of breast and ovarian cancer. During S phase of the cell cycle, BRCA1 polypeptides are found in discrete nuclear bodies (`BRCA1 nuclear dots') together with HsRad51, a human homolog of the E. coli recA protein, and BARD1, a protein that interacts with BRCA1 to form a stable heterodimer. BARD1 is structurally similar to BRCA1 in that both molecules harbor an amino-terminal RING domain and two carboxy-terminal BRCT domains. Here we describe the amino acid sequence and expression pattern of murine Bard1. A comparison of the mouse and human sequences reveals that the recognizable protein motifs of BARD1 are well conserved, including the RING domain, the three tandem ankyrin repeats, and, to a lesser extent, the two BRCT domains. However, the remaining sequences of BARD1 display a markedly lower degree of phylogenetic conservation, comparable to those reported for BRCA1 and BRCA2. Moreover, murine Bard1 retains the ability to associate in vivo with BRCA1, and its expression pattern in adult mice mirrors that of Brca1, with elevated levels of RNA transcripts found in the testes and spleen. These data suggest that BRCA1 and BARD1 have co-evolved to participate in a common pathway of tumor suppression.

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Involvement of Brca2 in DNA Repair

Cited by 566 publications

References 57 publications

p53 mutation with frequent novel codons but not a mutator phenotype in BRCA1- and BRCA2-associated breast tumours

p53 mutation with frequent novel codons but not a mutator phenotype in BRCA1- and BRCA2-associated breast tumours

DSS1 is required for the stability of BRCA2

Conservation of function and primary structure in the BRCA1-associated RING domain (BARD1) protein

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