Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P43146 (tumour suppressor)
 5,935 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The formation of RAD51 foci in response to ionizing radiation (IR) represents an important step in the repair of DNA double-strand breaks. RAD51 foci also appear during S phase and are thought to be required for the restart of stalled or broken replication forks. The RAD51 recombinase interacts directly with the breast cancer-associated tumour suppressor BRCA2, an interaction that is required for normal recombination proficiency, radiation resistance and genome stability. In CAPAN-1 cells, which express a truncated form of BRCA2 that is cytoplasmic because of loss of the nuclear localization signal, the formation of IR-induced RAD51 foci is impaired. In this work, we show that S-phase RAD51 foci form normally in CAPAN-1 cells expressing truncated BRCA2. Moreover, we find that RAD51 specifically associates with chromatin at S phase in a reaction that is BRCA2-independent. The observed BRCA2-dependent and independent formation of RAD51 foci shows that intact BRCA2 is not required for RAD51 focus formation per se, leading us to suggest that S phase and IR-induced RAD51 foci assemble by distinct pathways with defined protein requirements.
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PMID:BRCA2-dependent and independent formation of RAD51 nuclear foci. 1260 39

Most tumour suppressor genes (TSGs) have been found through linkage studies in cancer predisposed families where the mutations have a high penetrance, for example, the breast cancer genes BRCA1 and BRCA2. Loss of heterozygosity (LOH) analyses of sporadic breast tumours indicate that there are many other putative TSGs yet to be identified. One such locus is proximal to BRCA1 on human chromosome 17q21. In an attempt to isolate this putative TSG, we have assessed a portion of the orthologous region on mouse chromosome 11 for its tumorigenic potential using segmental haploidy in combination with a p53 mutation. Two populations of animals were studied, with the deleted region being either on the same (cis) or on the homologous chromosome (trans) to a targeted mutant p53 allele. The deficiency elevated the tumour susceptibility of p53 heterozygous mice and modified the tumour spectrum, but only when the deficiency was in trans with the p53 mutation. Even though the genotype of these mice is identical, allelic phasing affects both the tumour spectrum and progression.
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PMID:Allelic phasing of a mouse chromosome 11 deficiency influences p53 tumorigenicity. 1276 99

Germline mutations in the human checkpoint gene, hCHK2, were first identified in 1999 in cases of Li-Fraumeni syndrome. Recent studies have demonstrated that the hCHK2 1100delC mutation acts as a low-penetrance tumour suppressor gene in familial breast cancer not associated with mutations in BRCA1 or BRCA2. The present article describes the published studies on hCHK2 1100delC and addresses some of the key questions raised.
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PMID:Familial breast cancer and the hCHK2 1100delC mutation: assessing cancer risk. 1279 91

Heterozygous carriers of mutations in the BRCA2 gene have a high risk of developing breast and other cancers. In these individuals, BRCA2 appears to act as a tumour suppressor gene, in that loss of the wild type allele is frequently observed within tumours, leading to loss of BRCA2 function. Because BRCA2 functions in DNA repair via homologous recombination, this leads to genomic instability. However, it is unclear whether loss of the wild type allele is stochastic or if heterozygosity for BRCA2 mutation carries a phenotype that contributes to tumorigenic progression. Here we demonstrate that, in a specific vertebrate cell type, the chicken B cell line DT40, heterozygosity for a BRCA2 mutation has a distinct phenotype. This is characterized by a reduced growth rate, increased cell death, heightened sensitivity to specific DNA damaging agents and reduced RAD51 focus formation after irradiation. Thus in certain cell types, genome instability might be driven directly by heterozygosity for BRCA2 mutation.
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PMID:Phenotypic effects of heterozygosity for a BRCA2 mutation. 1292 78

Cancer is a genetic disease. Breast cancer tumorigenesis can be described as a multi-step process in which each step is thought to correlate with one or more distinct mutations in major regulatory genes. The question addressed is how far a multi-step progression model for sporadic breast cancer would differ from that for hereditary breast cancer. Hereditary breast cancer is characterized by an inherited susceptibility to breast cancer on basis of an identified germline mutation in one allele of a high penetrance susceptibility gene (such as BRCA1, BRCA2, CHEK 2, TP53 or PTEN). Inactivation of the second allele of these tumour suppressor genes would be an early event in this oncogenic pathway (Knudson's "two-hit" model). Sporadic breast cancers result from a serial stepwise accumulation of acquired and uncorrected mutations in somatic genes, without any germline mutation playing a role. Mutational activation of oncogenes, often coupled with non-mutational inactivation of tumour suppressor genes, is probably an early event in sporadic tumours, followed by more, independent mutations in at least four or five other genes, the chronological order of which is likely less important. Oncogenes that have been reported to play an early role in sporadic breast cancer are MYC, CCND1 (Cyclin D1) and ERBB2 (HER2/neu). In sporadic breast cancer, mutational inactivation of BRCA1/2 is rare, as inactivation requires both gene copies to be mutated or totally deleted. However, non-mutational functional suppression could result from various mechanisms, such as hypermethylation of the BRCA1 promoter or binding of BRCA2 by EMSY. In sporadic breast tumorigenesis, at least three different pathway-specific mechanisms of tumour progression are recognizable, with breast carcinogenesis being different in ductal versus lobular carcinoma, and in well differentiated versus poorly differentiated ductal cancers. Thus, different breast cancer pathways emerge early in the process of carcinogenesis, ultimately leading to clinically different tumour types. As mutations acquired early during tumorigenesis will be present in all later stages, large-scale gene expression profiling using DNA microarray analysis techniques can help to classify breast cancers into clinically relevant subtypes.
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PMID:Oncogenic pathways in hereditary and sporadic breast cancer. 1943 86

The BRCA2 tumour suppressor protein is involved in maintaining genetic stability through its role in homologous recombination (HR), where it mediates RAD51-dependent strand invasion. Here, we show that BRCA2-defective cells are not completely impaired in HR by strand invasion although the spontaneous HR rate is 10-fold lower than that in wild-type cells. Furthermore, a DNA double-strand break (DSB) triggers HR repair by strand invasion also in BRCA2-defective cells, but less efficiently. Thus, either the strand invasion pathway(s) in which BRCA2 operates is still operative in the absence of a functional BRCA2, albeit at a reduced frequency, or there is a separate pathway for strand invasion still functional in BRCA2-deficient cells. Consistent with the latter hypothesis, we show that HR events occurring in BRCA2-defective cells differ from HR events in wild-type cells. These data suggest that BRCA2-defective hamster cells are impaired in short tract gene conversion but maintain proficiency in sister chromatid exchange.
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PMID:Strand invasion involving short tract gene conversion is specifically suppressed in BRCA2-deficient hamster cells. 1548 Apr 13

The BRCA2 tumour suppressor is essential for the error-free repair of double-strand breaks (DSBs) in DNA by homologous recombination. This is mediated by RAD51, which forms a nucleoprotein filament with the 3' overhanging single-stranded DNA (ssDNA) of the resected DSB, searches for a homologous donor sequence, and catalyses strand exchange with the donor DNA. The 3,418-amino-acid BRCA2 contains eight approximately 30-amino-acid BRC repeats that bind RAD51 (refs 5, 6) and a approximately 700-amino-acid DBD domain that binds ssDNA. The isolated BRC and DBD domains have the opposing effects of inhibiting and stimulating recombination, respectively, and the role of BRCA2 in repair has been unclear. Here we show that a full-length BRCA2 homologue (Brh2) stimulates Rad51-mediated recombination at substoichiometric concentrations relative to Rad51. Brh2 recruits Rad51 to DNA and facilitates the nucleation of the filament, which is then elongated by the pool of free Rad51. Brh2 acts preferentially at a junction between double-stranded DNA (dsDNA) and ssDNA, with strict specificity for the 3' overhang polarity of a resected DSB. These results establish a BRCA2 function in RAD51-mediated DSB repair and explain the loss of this repair capacity in BRCA2-associated cancers.
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PMID:The BRCA2 homologue Brh2 nucleates RAD51 filament formation at a dsDNA-ssDNA junction. 1570 34

The gene encoding the human BRCA2 tumour suppressor is mutated in a number of different tumour types, most notably inherited breast cancers. The primary role of BRCA2 is thought to lie in the maintenance of genomic stability via its role in the homologous recombination pathway. We generated mice in which Brca2 was deleted from virtually all cells within the adult small intestine, using a CYP1A1-driven Cre-Lox approach. We noted a significant p53-dependent increase in the levels of spontaneous apoptosis which persisted for several months after removal of the gene and ultimately we observed the spontaneous deletion of Brca2-deficient stem cells. Brca2 deficiency did not lead to gross changes in intestinal physiology but did enhance sensitivity to a variety of DNA crosslinking agents. Taken together, our results indicate that Brca2 plays an important role in the response to DNA damage in the small intestine. Furthermore, we show that Brca2 deficiency results in the spontaneous deletion of stem cells, thereby protecting the small intestine against tumorigenesis.
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PMID:Brca2 deficiency in the murine small intestine sensitizes to p53-dependent apoptosis and leads to the spontaneous deletion of stem cells. 1573 71

Since the discovery of the tumour suppressor BRCA2 (encoded by breast-cancer susceptibility gene 2), cells lacking the fully functional protein have consistently been found to show increased sensitivity to a variety of DNA-damaging agents, particularly those that cross-link DNA. In this short review, we will bring together these findings and discuss them in the light of our recent in vivo data in the mouse small intestine, which suggests that deletion of cells lacking Brca2 is necessary to avoid the development of potentially tumorigenic clones in this tissue, a system that may be less effective in the mammary glands of humans with germline mutations in BRCA2.
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PMID:DNA damage hypersensitivity in cells lacking BRCA2: a review of in vitro and in vivo data. 1604 82

Human DSS1 associates with BRCA2, a tumour suppressor protein required for efficient recombinational DNA repair, but the biochemical function of DSS1 is not known. Orthologues of DSS1 are found in organisms such as budding yeast and fission yeast that do not have BRCA2-related proteins, indicating that DSS1 has a physiological role independent of BRCA2. The DSS1 orthologue in Saccharomyces cerevisiae has been shown to associate with the 26 S proteasome and, in the present paper, we report that in the distantly related fission yeast Schizosaccharomyces pombe, Dss1 associates with the 19 S RP (regulatory particle) of the 26 S proteasome. A role for S. pombe Dss1 in proteasome function is supported by three lines of evidence. First, overexpression of two components of the 19 S RP, namely Pad1/Rpn11 and Mts3/Rpn12, rescued the temperature-sensitive growth defect of the dss1 mutant. Secondly, the dss1 mutant showed phenotypes indicative of a defect in proteasome function: growth of the dss1 mutant was inhibited by low concentrations of L-canavanine, an amino acid analogue, and cells of the dss1 mutant accumulated high molecular mass poly-ubiquitylated proteins. Thirdly, synthetic growth defects were found when the dss1 mutation was combined with mutations in other proteasome subunit genes. These findings show that DSS1 has an evolutionarily conserved role as a regulator of proteasome function and suggest that DSS1 may provide a link between BRCA2 and ubiquitin-mediated proteolysis in human cells.
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PMID:Fission yeast Dss1 associates with the proteasome and is required for efficient ubiquitin-dependent proteolysis. 1614 16


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