BRCA1-directed, enhanced and aberrant homologous recombination

Abstract

Despite intense studies, questions still remain regarding the molecular mechanisms leading to the development of hereditary breast and ovarian cancers. Research focused on elucidating the role of the breast cancer susceptibility gene 1 (BRCA1) in the DNA damage response may be of the most critical importance to understanding these processes. The BRCA1 protein has an N-terminal RING domain possessing E3 ubiquitinligase activity and a C-terminal BRCT domain involved in binding specific phosphoproteins. These domains are involved directly or indirectly in DNA double-strand break (DSB) repair. As the two terminal domains of BRCA1 represent two separate entities, understanding how these domains communicate and are functionally altered in regards to DSB repair is critical for understanding the development of BRCA1-related breast and ovarian cancers and for developing novel therapeutics. Herein, we review recent findings of how altered functions of these domains might lead to cancer through a mechanism of increased aberrant homologous recombination and possible implications for the development of BRCA1 inhibitors.

The predictive value of 53BP1 and BRCA1 mRNA expression in advanced non-small-cell lung cancer patients treated with first-line platinum-based chemotherapy

“…In particular, aberrations of the Mre11-Rad50-Nbs1 (MRN) complex sensitized cells to PARP inhibition, even in BRCA1-2 wild-type tumors [39]. The potential therapeutic applications of synthetic lethality models could involve the clinical development of PARP inhibitors in the setting of molecularly-driven disease as well as the use of molecules inhibiting specific BRCA1 protein domains [5]. …”

“…BRCA1 is also a main component of DNA double-strand break repair through the error-free mechanism of homologous recombination [4]. The pivotal role of BRCA1 in double-strand break repair may be modulated by interaction with other components of homologous recombination [5]. In preclinical models, BRCA1 expression conferred resistance to cisplatin and sensitivity to taxanes [6-10], and its predictive role has been confirmed in several solid tumors, including NSCLC [11-15].…”

DNA Double-Strand Break Repair as Determinant of Cellular Radiosensitivity to Killing and Target in Radiation Therapy

“…These observations are further supported by results showing decreased survival of irradiated BRCA1 −/− mouse embryonic fibroblasts exposed to IR and emphasize the central role of HRR in the maintenance of genomic integrity. Notably, more recent results suggest that inactivation of BRCA1 ubiquitin-ligase activity up-regulates protein complexes involved in DNA end-resection, causing elevated but aberrant HRR that undermines genomic instability (Drost et al, 2011; Dever et al, 2012). Along these lines, C61G mutation in the BRCA1 gene is associated with complete loss of BRCA1 E3-ubiquitin-ligase function, and disruption of the BRCA1/BARD1 complex, which results in increased formation of RAD51 foci, and abnormal rate of HRR (Drost et al, 2011).…”

Peptide Library Approach to Uncover Phosphomimetic Inhibitors of the BRCA1 C-Terminal Domain

“…These Asp/Glu-x-x-4FPhe motifs are quite similar to the pSer-x-x-Phe motif shared by all known BRCA1 (BRCT) 2 -domain binding proteins. 37 Previously oriented SPOT library screens have shown that peptides containing β -branched and aromatic AAs in the x-x positions show enhanced binding. 13 This preference is also mirrored in many of our sequences.…”