RAD51 paralogs: Expanding roles in genome maintenance and tumor suppression
Prof. Ganesh Nagaraju, Department Of Biochemistry, Indian Institute Of Science
LS Seminar Hall
Date & Time
22 Sep 2023 16:00 hrs
Santosh Kumar #2787
RAD51 recombinase plays a central role in homologous recombination (HR) mediated repair of DNA double-strand breaks (DSBs). Mammalian cells encode five RAD51 paralogs: RAD51B, RAD51C, RAD51D, XRCC2 and XRCC3. These paralogs have been implicated in repair of DSBs by HR and DNA damage signaling. Germline mutations in RAD51 paralogs leads to breast and ovarian cancers as well as Fanconi anemia (FA)-like disorder. Using pathological RAD51C mutants our lab showed that RAD51C distinctly regulates DNA damage signaling and repair. We showed that RAD51C binding partner XRCC3 S225 undergoes phosphorylation in an ATM/ATR kinase dependent manner and this phosphorylation is crucial for the execution of intra-S-phase checkpoint and DSB repair by HR. In an effort to understand the essential roles of RAD51 paralogs, our investigations revealed that RAD51 paralogs in distinct complexes regulate replication fork stability and its restart. We also demonstrated a repair independent function of XRCC2 restraining pathological fork progression during dNTP alterations and safeguards the genome integrity. The fork restraining function is dependent on XRCC2 S247 phosphorylation by ATR kinase. When the fork collapses in the absence of XRCC2 or its phosphorylation, we find an early activation of XRCC3 by ATR which promotes cell survival and genome integrity. Together, these data provide evidence for the new roles of RAD51 paralogs in genome maintenance and tumor suppression.