BRCA1 and its toolbox for the maintenance of genome integrity

Abstract

The breast and ovarian cancer type 1 susceptibility protein (BRCA1) has pivotal roles in the maintenance of genome stability. Studies support that BRCA1 exerts its tumour suppression function primarily through its involvement in cell cycle checkpoint control and DNA damage repair. In addition, recent proteomic and genetic studies have revealed the presence of distinct BRCA1 complexes in vivo, each of which governs a specific cellular response to DNA damage. Thus, BRCA1 is emerging as the master regulator of the genome through its ability to execute and coordinate various aspects of the DNA damage response.

Distinct Roles of FANCO/RAD51C Protein in DNA Damage Signaling and Repair

“…BRCA1 tumor suppressor is known to have multiple functions, including its roles in DNA damage signaling, HR, and genome stability, and these functions have been implicated in tumor suppressor function (55). BRCA1 exists in multiple complexes, and these complexes are known to have independent as well as overlapping functions in genome maintenance (55).…”

ATM-dependent Phosphorylation of the Fanconi Anemia Protein PALB2 Promotes the DNA Damage Response

“…PALB2 physically links BRCA1 and BRCA2 and plays an important role in HR repair (5). Interestingly, we found that BRCA1 promoted PALB2 phosphorylation at Ser-157, whereas phosphorylation of PALB2 Ser-376 was only marginally affected in the absence of BRCA1 (Fig.…”

“…Together with BRCA2, the PALB2-BRCA2 heterodimeric complex initiates high-fidelity homologous recombination (HR) 4 DNA repair by promoting the assimilation of the recombinase RAD51 onto resected 3Ј single-strand overhangs (1)(2)(3). Inactivation of PALB2 compromised RAD51 loading onto DNA breaks, greatly diminished HR repair, and hyper-sensitized cells to genotoxic stress (4,5). Consistent with the intimate links between dysregulated DNA repair and human tumorigenesis, PALB2 mutations predispose individuals to early onset of a number of cancers, including those of breast and pancreatic origins (6 -10).…”

BRCA1promotes the ubiquitination of PCNA and recruitment of translesion polymerases in response to replication blockade

“…In humans, many factors involved in DDR and DNA repair, such as BRCA1 and BRCA2, are wellknown tumor suppressors. BRCA1 has been linked to both familial and sporadic breast and ovarian cancers, and it operates in multiple biological pathways including DDR and DNA repair (2,3). BRCA1 is essential for the homologous recombination (HR) repair pathway, and therefore, cells deficient in BRCA1 function are hypersensitive to ionizing radiation and other drugs that directly induce double-strand breaks (DSBs) (4).…”