Special Centre for Molecular Medicine
Jawaharlal Nehru University
Seminar Notice
Title: RAD51 paralogs: unraveling the new roles in genome stability and tumor suppression
Dr. Ganesh Nagaraju
Associate Professor
Dept. of Biochemistry; Indian Institute of Science, Bangalore
Abstract: 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. Mouse knockout of any one paralogs leads to embryonic lethality, implying the essential functions of RAD51 paralogs in genome maintenance. Recent studies show that germline mutations in RAD51 paralogs cause 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. Our recent work shows that XRCC2 restrains 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.
Date: Thursday 14 November, 2019
Time: 11.00 AM
Venue: Seminar Hall, SCMM
All are welcome