"Defects in the BRCA1 or BRCA2 genes are responsible for most hereditary forms of breast cancer and account for as many as 10% of all breast cancer cases . Women with a strong family history of cancer who possess a harmful BRCA1 or BRCA2 allele are at high risk for developing breast cancer within their lifetime (80% and 60%, respectively) [2,3]. In addition, BRCA1 mutation carriers have a 30-40% chance of developing ovarian cancer, while BRCA2 mutations also increase the risk of ovarian, pancreatic, prostate, and male breast cancer . "
[Show abstract][Hide abstract] ABSTRACT: Background
The maintenance of chromosomal integrity is an essential task of every living organism and cellular repair mechanisms exist to guard against insults to DNA. Given the importance of this process, it is expected that DNA repair proteins would be evolutionarily conserved, exhibiting very minimal sequence change over time. However, BRCA1, an essential gene involved in DNA repair, has been reported to be evolving rapidly despite the fact that many protein-altering mutations within this gene convey a significantly elevated risk for breast and ovarian cancers.
To obtain a deeper understanding of the evolutionary trajectory of BRCA1, we analyzed complete BRCA1 gene sequences from 23 primate species. We show that specific amino acid sites have experienced repeated selection for amino acid replacement over primate evolution. This selection has been focused specifically on humans and our closest living relatives, chimpanzees (Pan troglodytes) and bonobos (Pan paniscus). After examining BRCA1 polymorphisms in 7 bonobo, 44 chimpanzee, and 44 rhesus macaque (Macaca mulatta) individuals, we find considerable variation within each of these species and evidence for recent selection in chimpanzee populations. Finally, we also sequenced and analyzed BRCA2 from 24 primate species and find that this gene has also evolved under positive selection.
While mutations leading to truncated forms of BRCA1 are clearly linked to cancer phenotypes in humans, there is also an underlying selective pressure in favor of amino acid-altering substitutions in this gene. A hypothesis where viruses are the drivers of this natural selection is discussed.
"Its encoded protein has 3 major domains, including (1) an N-terminal RING finger domain (BRCA1 RING domain), (2) a large central segment with the nuclear localization signal (NLS), and (3) the BRCA1 C-terminal domain (BRCT). The BRCA1 protein plays an essential role in maintaining genomic stability associated with a number of cellular processes, including DNA repair, a cell cycle checkpoint, transcriptional regulation, and protein ubiquitination.4,5 "
[Show abstract][Hide abstract] ABSTRACT: The breast cancer susceptibility gene 1 (BRCA1) has been shown to maintain genomic stability through multiple functions in the regulation of DNA damage repair and transcription. Its translated BRCT (BRCA1 C-terminal domain) acts as a strong transcriptional activator. BRCA1 damaged by carboplatin treatment may lead to a loss of such functions. To address the possibility of the BRCA1 gene as a therapeutic target for carboplatin, we investigated the functional consequences of the 3'-terminal region of human BRCA1 following in vitro platination with carboplatin. A reduction in cellular BRCA1 repair of carboplatin-treated plasmid DNA, using a host cell reactivation assay, was dependent on the platination levels on the reporter gene. The transcriptional transactivation activity of the drug-modified BRCA1, assessed using a one-hybrid GAL4 transcriptional assay, was inversely proportional to the carboplatin doses. The data emphasized the potential of the BRCA1 gene to be a target for carboplatin treatment.
Breast cancer 03/2014; 8(1):51-6. DOI:10.4137/BCBCR.S14224
"To form an acentric fragment, DNA DSBs should either occur in one sister chromatid or extend to the whole anaphase chromosome (Figure 3). This happens only if the level of DSBs exceeds the repair capacity of dividing cells, which is mainly due to either the misrepair of DSBs by the dysfunctional homologous recombination (HR; O’Donovan and Livingston, 2010) or defects in enzymes of the non-homologous end-joining (NHEJ) pathway (Hartlerode and Scully, 2009). The formation of DNA DSBs and MN is often the result of simultaneous excision repair of damages and wrong base incorporation. "
[Show abstract][Hide abstract] ABSTRACT: Micronuclei (MN) are extra-nuclear bodies that contain damaged chromosome fragments and/or whole chromosomes that were not incorporated into the nucleus after cell division. MN can be induced by defects in the cell repair machinery and accumulation of DNA damages and chromosomal aberrations. A variety of genotoxic agents may induce MN formation leading to cell death, genomic instability, or cancer development. In this review, the genetic and epigenetic mechanisms of MN formation after various clastogenic and aneugenic effects on cell division and cell cycle are described. The knowledge accumulated in literature on cytotoxicity of various genotoxins is precisely reflected and individual sensitivity to MN formation due to single gene polymorphisms is discussed. The importance of rapid MN scoring with respect to the cytokinesis-block micronucleus assay is also evaluated.
Frontiers in Genetics 07/2013; 4:131. DOI:10.3389/fgene.2013.00131
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