BRCA1 Breast Cancer Susceptibility Gene Product

In the search for a mammalian homolog of Rad9, three proteins were found to share significant homology with the BRCT motifs of scRad9 - BRCA1, MDC1 and 53BP1. BRCA1 was identified in 1994 as the product of a gene that acted as a tumor suppressor in breast and ovarian cancer. Since then hundreds of mutations have been found in affected families and 80% of individuals carrying BRCA1 defects succumb to these diseases.

In terms of the DNA damage response, BRCA1 contains two C-terminal BRCT repeats which have homology with the BRCT domains of Rad9 from S. cerevisiae suggesting a role for BRCA1 in checkpoint signalling and DNA repair. It has also been demonstrated to have binding affinities with a large number of proteins that function in checkpoint activation and transcription, including the ATR kinase, PP1a protein phosphatase (Liu et al. 2002), SWI/SNF chromatin remodelling complexes (Bochar et al. 2000), the c-myc oncogene (Li et al. 2002) and the BACH1 helicase (Peng, et al. 2006).

BRCA1 has also been reported to bind DNA through a central domain spanning residues 452—1,079 with preferential binding to branched DNA structures. Although, BRCA1 could influence DNA repair indirectly through its role in transcription, its affinity for branched DNA and the MRN complex in particular suggesting that BRCA1 has direct roles in DSB repair (Durant and Nickoloff 2005).

Furthermore, defects in BRCA1 confer sensitivity to a broad range of DNA damaging agents suggesting that BRCA1 is a central component of the DNA damage response mechanism (Westermark et al. 2003; Zhang et al. 2004). It has also been shown that BRCA1 is required for ATM- and ATR-dependent phosphorylation of p53, c-Jun, Nbs1 and Chk2 following exposure to IR or UV radiation, respectively (Foray et al. 2003). However, BRCA1 appears to be dispensable for DNA damage induced phosphoryla-tion of components of the checkpoint sliding clamp (hRad9, hRad1 and hHus1) as well as relocalization of this complex to DNA lesions. Foray et al. go on to propose that BRCA1 facilitates the ability of ATM and ATR to phosphorylate downstream substrates that directly influence cell cycle checkpoint arrest and apoptosis, but that BRCA1 is dispensable for the phosphorylation of DNA associated ATM and ATR substrates. These studies suggest that BRCA1 could be acting as a specific scaffold for the two PIKKs to phosphorylate a specific subset of their substrates.

As outlined, BRCA1 has been reported to have a number of roles in the DNA damage response, and its two C-terminal BRCT domains do share sequence homology with scRad9, however, recent reports about another putative ortholog-53BP1 suggest that this protein could have more functional homology to scRad9 than either BRCA1 or MDC1.

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