Work

A Variant of the Breast Cancer Type 2 Susceptibility Protein (BRC) Repeat Is Essential for the RECQL5 Helicase to Interact with RAD51 Recombinase for Genome Stabilization

Year: 2012

Type: article

Abstract: The BRC repeat is a structural motif in the tumor suppressor BRCA2 (breast cancer type 2 susceptibility protein), which promotes homologous recombination (HR) by regulating RAD51 recombinase activity. To date, the BRC repeat has not been observed in other proteins, so that its role in HR is inferred only in the context of BRCA2. Here, we identified a BRC repeat variant, named BRCv, in the RECQL5 helicase, which possesses anti-recombinase activity in vitro and suppresses HR and promotes cellular resistance to camptothecin-induced replication stress in vivo . RECQL5-BRCv interacted with RAD51 through two conserved motifs similar to those in the BRCA2-BRC repeat. Mutations of either motif compromised functions of RECQL5, including association with RAD51, inhibition of RAD51-mediated D-loop formation, suppression of sister chromatid exchange, and resistance to camptothecin-induced replication stress. Potential BRCvs were also found in other HR regulatory proteins, including Srs2 and Sgs1, which possess anti-recombinase activities similar to that of RECQL5. A point mutation in the predicted Srs2-BRCv disrupted the ability of the protein to bind RAD51 and to inhibit D-loop formation. Thus, BRC is a common RAD51 interaction module that can be utilized by different proteins to either promote HR, as in the case of BRCA2, or to suppress HR, as in RECQL5. Background: The BRC repeat is essential for BRCA2 to bind RAD51 and promote homologous recombination. Results: A BRC repeat variant is essential for RECQL5 to bind RAD51 and suppress homologous recombination. Conclusion: The BRC repeat can be utilized to either promote or suppress homologous recombination. Significance: Discovery of multiple functions of the BRC repeat is important for understanding regulation of homologous recombination.

Source: Journal of Biological Chemistry

DOI: 10.1074/jbc.m112.375014