Biology

Dr. Ganesh Nagaraju
Dept. of Biochemistry Indian Institute of Science, Bagalore

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. In addition, RAD51, RAD51C and XRCC3 have been shown to localize to mitochondria and contribute to stability of the mitochondrial genome (mtDNA) during oxidative stress. 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 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 showed that RAD51C and XRCC3 facilitates mitochondrial DNA replication and maintains the stability of mitochondrial genome. 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. Together, these data provide evidence for the new roles of RAD51 paralogs in genome maintenance and tumor suppression.