How do mutations affecting the breast cancer genes BRCA1 and BRCA2 cause cancer susceptibility?

Abstract

The inheritance of monoallelic germline mutations affecting BRCA1 or BRCA2 predisposes with a high penetrance to several forms of epithelial malignancy. The large, nuclear-localized BRCA proteins act as custodians of chromosome integrity through distinct functions in the assembly and activity of macromolecular complexes that mediate DNA repair, replication reactivation and mitotic progression. The loss of these tumour suppressive functions following biallelic BRCA gene inactivation has long been thought to provoke genomic instability and carcinogenesis. However, recent studies not only identify new functions for BRCA1 and BRCA2 in the regulation of transcription and RNA processing potentially relevant to their tumour suppressive activity, but also suggest that monoallelic BRCA2 gene mutations suffice for carcinogenesis. This emerging evidence opens fresh lines of enquiry concerning tissue-specific cancer evolution in BRCA mutation carriers. Collectively, these insights engender new models to explain how BRCA gene mutations cause cancer susceptibility in specific tissues.

Keywords: BRCA1; BRCA2; Carcinogenesis; Chromosome stability; DNA repair; DNA replication; R-loops; Transcription.

Figure 1. The human BRCA1 and BRCA2 proteins.

The schematics representing human BRCA1 (1863 amino acids) and BRCA2 (3418 amino acids) are not to the same scale. Regions depicted as white boxes in BRCA1 include the N-terminal RING domain, the C-terminal tandem BRCT (tBRCT) domains, and a region predicted to encode coiled coil (CC) motifs. Regions depicted in BRCA2 include the conserved region of exon 11 encoding 8 repeats of the 30-40 amino acid BRC motif (white line), as well as the adjoining helical domain (HD, white box), and OB1-3 folds (white box), which together form a DNA-binding domain. The segments binding DSS1 (DSS1-b) and encoding the tower domain (TD) are represented as black lines. Proposed mutation cluster regions predisposing preferentially to breast (BCCR, green) or ovarian (OvCCR, red) are shown, based on data from Rebbeck et al., 2015. Caveats concerning the nature and mechanism of the proposed cluster regions are summarized in the main text.

Figure 2. R-loop accumulation and chromosome instability in BRCA-deficient cells.

The schematic depicts how transcription-associated R loop accumulation in BRCA2-deficient cells may be a major source of replication stress and DNA damage leading to chromosome fragility. Roles are shown for BRCA1 and BRCA2 in R-loop turnover at the promoter-proximal pausing (PPP) sites, or at transcription termination (TT) sequences, of expressed genes. The RNAPII regulatory factors PAF1 and NELFB work with BRCA2 and BRCA1 respectively, in the switch from pausing to elongation. Senataxin (SETX) is recruited by BRCA1 to TT sites. The ERCC4/ERCC5 nuclease has been implicated in R-loop cleavage to form DNA breaks.