Multifaceted roles of PDS5B in RAD51-dependent homology-directed DNA repair and replication fork protection

PDS5B (Precocious Dissociation of Sisters 5B) functions in sister chromatid cohesion and genome organization. Interestingly, PDS5B also associates with RAD51, the recombinase required for DNA damage repair by homologous recombination (HR) and the preservation of stressed DNA replication forks against nucleolytic attrition. We show that PDS5B binds dsDNA preferentially over ssDNA and that it enhances RAD51-mediated DNA strand exchange via the capture of dsDNA. PDS5B also acts synergistically with BRCA2-DSS1 to help overcome the interference of RPA in DNA strand exchange and works in conjunction with RAD51 to protect dsDNA against digestion by MRE11-RAD50-NBS1. DNA binding activity resides within the disordered C-terminal region of PDS5B, and testing of a DNA binding mutant provides evidence that this PDS5B attribute underpins protein functions in vitro and in HR and replication fork protection in cells. Our findings thus reveal distinct functions of PDS5B in genome repair and maintenance. PDS5B, a cohesin regulatory protein, is shown to bind DNA and enhance the RAD51 recombinase in the promotion of DNA strand exchange and protection of DNA from MRE11 RAD50-NBS1. Here the authors use biochemical and cellular analyses to reveal that DNA binding by PDS5B is essential for DNA damage repair and the preservation of stressed DNA replication forks.