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)

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 recombination-mediated 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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PMID:BRCA2: a universal recombinase regulator. 1806 84

Germline mutations in the BRCA2 tumour suppressor gene are significant risk indicators of breast cancer in women, especially for hereditary breast cancer. The BRCA2 protein interacts via the BRC (breast cancer) domain with RAD51, an essential component of the cellular machinery for the maintenance of genome stability and double strand-breaks repair. Exon 11 is the largest exon of the BRCA2 gene and contains the region encoding eight repeats of the BRC domain. Little is known about the roles of BRCA2 exon 11 in canine mammary tumours. In present study, the entire BRCA2 exon 11 was sequenced in canine mammary tumours. Fifteen mammary gland samples were obtained from four normal mammary glands and 11 mammary tumours (10 malignant and one benign tumours). Comparing sequences of normal mammary glands with those in GenBank (AB043895 and Z75664), a single nucleotide polymorphism (SNP) at codon 2414 G>A (resulting in a lysine to an arginine substitution) was identified. When compared with the normal mammary gland, 19 sporadically distributed point mutations were found in mammary tumours, including 68% of missense and 32% of silent mutations. A high frequency of genetic variations in codon 511 A>C or 2414 A>G were identified in 6/11 cases, and two missense mutations (2414 A>G, 2383 A>C) were located at the fourth repeat of the BRC domains.
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PMID:Single nucleotide variation in exon 11 of canine BRCA2 in healthy and cancerous mammary tissue. 1994 33

Chromosomal instability is a hallmark of human cancer cells, but its role in carcinogenesis remains poorly resolved. Insights into this role have emerged from studies on the tumour suppressor BRCA2, whose inactivation in human cancers causes chromosomal instability through the loss of essential functions of the BRCA2 protein in the normal mechanisms responsible for the replication, repair and segregation of DNA during cell division. Humans who carry heterozygous germline mutations in the BRCA2 gene are highly predisposed to cancers of the breast, ovary, pancreas, prostate and other tissues. Here, we review recent studies that describe genetically engineered mouse models (GEMMs) for pancreatic cancer associated with BRCA2 mutations. These studies not only surprisingly show that BRCA2 does not follow the classical Knudson "two hit" paradigm for tumour suppression, but also highlight features of the interplay between TP53 inactivation and carcinogenesis in the context of BRCA2 deficiency. Thus, the models reveal novel aspects of cancer evolution in carriers of germline BRCA2 mutations, provide new insights into the tumour suppressive role of BRCA2, and establish valuable new preclinical settings for testing approaches to pancreatic cancer therapy; together, these features emphasize the value of GEMMs in cancer research.
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PMID:Chromosome instability and carcinogenesis: insights from murine models of human pancreatic cancer associated with BRCA2 inactivation. 2426 22