Figure 6.

The role of BRCA2 in response to replication stress produced by hydroxyurea and DNA interstrand cross-links is distinct. Schematic representing the different roles of BRCA2 in replication fork protection and homologous recombination. (A) During homologous recombination repair of DSBs, BRCA2 assembles RAD51 nucleofilaments onto ssDNA overhangs, which is important for the RAD51-mediated homology search of the sister chromatid. (B) During DNA interstrand cross-link repair, homologous recombination is required to repair the programmed DSBs. BRCA2 has a role in two distinct types of replication fork protection. (C) At HU stalled forks, replication fork remodeling depends on RAD51 and the SNF2 translocases, SMARCAL1, ZRANB3, and HLTF. BRCA2 and RAD51 protect the reversed replication fork from degradation by nucleases. The MRE11 nuclease has been reported numerous times to be responsible for the degradation of HU stalled forks in the absence of fork protection. More recently, other nucleases have been described in nascent strand degradation including EXO1 and DNA2. (D) At ICLs, BRCA2 and RAD51 protect the fork from resection by the DNA2-WRN nuclease helicase complex. The ssDNA generated after MMC is not dependent on MRE11, CTIP, or EXO1, as described for HU stalled forks. ICL repair does not require the function of the SNF2 translocases, suggesting that reversed forks present in MMC treated cells are likely the result of a more global cellular response to replication stress. We also propose that an additional role of the FA core complex and associated proteins at the ICL is to prevent aberrant resection by the DNA2–BLM nuclease helicase complex.