Abstract
A fraction of breast cancer cases are associated with mutations in the BRCA1 (BRCA1 DNA repair associated, breast cancer type 1 susceptibility protein) gene, whose mutated product may disrupt the repair of DNA double-strand breaks as BRCA1 is directly involved in the homologous recombination repair of such DNA damage. However, BRCA1 can stimulate nucleotide excision repair (NER), the most versatile system of DNA repair processing a broad spectrum of substrates and playing an important role in the maintenance of genome stability. NER removes carcinogenic adducts of diol-epoxy derivatives of benzo[α]pyrene that may play a role in breast cancer pathogenesis as their accumulation is observed in breast cancer patients. NER deficiency was postulated to be intrinsic in stage I of sporadic breast cancer. BRCA1 also interacts with GADD45A (growth arrest and DNA damage-inducible protein GADD45 alpha) that may target NER machinery to actively demethylate genome sites in order to change the expression of genes that may be important in breast cancer. Therefore, the interaction between BRCA1 and GADD45 may play a role in breast cancer pathogenesis through the stimulation of NER, increasing the genomic stability, removing carcinogenic adducts, and the local active demethylation of genes important for cancer transformation.
Highlights
Breast cancer, as is the case for many other, if not all, cancers, is underlined by genomic instability, which results from excessive DNA damage and/or an impaired DNA damage response (DDR)
Hartman and Ford showed that BRCA1 enhanced GG-nucleotide excision repair (NER) and induced the p53-independent expression of XPC, DDB2, and growth arrest and DNA damage-inducible 45 alpha (GADD45A) [70]. These authors found that BRCA1 selectively affected global genome NER (GG-NER) and the repair of non-transcribed strands in cells exposed to UV in a p53-independent manner
BRCA1 overexpression increased the repair of cyclobutane pyrimidine dimers (CPDs) by about 30%, whereas the repair of (6-4)PPs was not affected, but it should be noted that this kind of damage was completely removed independently of the p53 and BRCA1 status
Summary
As is the case for many other, if not all, cancers, is underlined by genomic instability, which results from excessive DNA damage and/or an impaired DNA damage response (DDR). DNA repair associated, breast cancer type 1 susceptibility) and BRCA2 genes (Figure 1) [1]. The presence of such variants increases the lifetime risk of breast cancer by 40–90% [2]. Several genome-protective functions have been attributed to BRCA1, including transcription regulation, DNA repair, chromatin remodeling, and ubiquitin ligation [4]. That role includes its involvement in cell cycle control, chromatin remodeling, remodeling, homologues recombination repair (HRR), and non-homologues end-joining (NHEJ) [4]. These include TP53 (tumor protein p53), PTEN (phosphatase and tensin homologue), localizer of BRCA2), NBN (Nibrin), ATM (ataxia telangiectasia mutated), BRIP1 interacting. Not changes all familial breast cancerepigenetic cases can be explained by the changes in genetic factors identified to date and changes in the heritable epigenetic profile play a role
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