Differing Clinical Impact of BRCA1 and BRCA2 Mutations in Serous Ovarian Cancer

Guoyan Liu; Da Yang; Yan Sun; Ilya Shmulevich; Fengxia Xue; Anil K Sood; Wei Zhang

Disclosures

Pharmacogenomics. 2012;13(13):1523-1535. 

In This Article

Different Roles of BRCA1 & BRCA2 in DNA-repair Pathway

The observed differences in clinical outcome basis of BRCA1 versus BRCA2 mutations may be rooted in different functions of these proteins in dsDNA-repair pathway. BRCA1 was first localized to chromosome 17 via a genetic linkage analysis[75] and was cloned in 1994.[76] The C-terminus of BRCA1 contains a BRCA1 C-terminal (BRCT) domain, which facilitates phosphoprotein binding. The N-terminus has a RING domain, which has E3 ubiquitin ligase activity. BRCA1 interacts with PALB2 through a domain toward the C-terminal region. Because PALB2 also interacts with BRCA2, BRCA1 may affect BRCA2 function through PALB2.[77]

BRCA2 was found to be related to hereditary breast cancer in 1995.[78] BRCA2 contains a DNA-binding domain, which binds both ssDNA and dsDNA. BRCA2 has eight BRC repeats that bind RAD51. The C-terminus of BRCA2 also binds RAD51 in a phosphorylation-regulated manner (Figure 1).[79–81]

Both BRCA1 and BRCA2 have been reported to play key roles in DNA-damage repair; however, they appear to have distinct but complementary functions. BRCA1 plays more diverse roles including sensing DNA damage and replication stress, mediating signaling responses, signaling cell cycle checkpoints and mediating other transcriptional responses to DNA damage.[82] In the homologous recombination pathway, BRCA1 is mainly a scaffold protein, enabling interactions between different components of the homologous recombination machinery, and is required for the initial steps of the dsDNA break-repair response and signal amplification. By contrast, BRCA2 is directly involved in loading RAD51 to damage sites or stalled replication forks.[83,84] BRCA2 acts by navigating RAD51 to ssDNA, enabling RAD51 to displace replication protein-A from ssDNA and stabilizing RAD51–ssDNA filaments by blocking ATP hydrolysis, which is a key regulatory step in DNA pairing.[85,86] RAD51 plays a central role in recombination, assembling onto ssDNA as a nucleoprotein filament and catalyzing the exchange of homologous DNA sequences.[87]

BRCA2's more direct involvement in homologous recombination is consistent with the association of BRCA2 mutations and hypermutator phenotype that the authors found in OC. Most BRCA2 mutations found in TCGA study were in the RAD51-binding domain or caused truncations that would delete the RAD51-binding region (Figure 1); therefore, these mutations are expected to attenuate or abolish the interaction with RAD51, resulting in failure to load RAD51 to DNA-damage sites. BRCA1 is also implicated in RAD51 recruitment to the sites of DNA damage through its interactions with PALB2 and BRCA2. This interaction appears to be dependent on CHK2-mediated phosphorylation of S988 on BRCA1.[82] Interestingly, most BRCA1 mutations do not result in deletion of S988 or the PALB2 interaction region that regulates BRCA2 (Figure 1); thus, BRCA1 mutation may have less impact on RAD51-mediated homologous recombination. Consistent with this notion, mutations on the C-terminal region of BRCA1, including the PALB2-binding region, were found to be correlated with better survival advantage by Bolton et al.[8] Thus, this group of BRCA1-mutated cases may impact survival in a manner similar to that BRCA2-mutated bases because of the effect of these mutants on BRCA2.

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