Ph.D.: Indian Institute of Science, Bangalore, India
Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, USA
Year of Joining: 2007
Our lab is broadly interested in understanding how various genes regulate DNA damage responses, maintain genome integrity and supress tumorigenesis.
Mammalian genome encodes five RAD51 paralogs (RAD51B, RAD51C, RAD51D, XRCC2 and XRCC3). We have established that RAD51C is a novel gene in the Fanconi anemia (FA) pathway of DNA interstrand cross-link (ICL) repair and demonstrated that RAD51C distinctly regulates intra-S-phase checkpoint and DNA repair. This finding has implications for FA and breast and ovarian cancer susceptibility. We have demonstrated that XRCC3 is a novel phosphorylation target of ATM and ATR kinases which is crucial for execution of DNA repair and intra-S-phase checkpoint. We showed new roles of RAD51 paralogs in the protection and restart of stalled forks. Our study with pathological mutants of RAD51C provided insights into tumor suppressor and essential functions of RAD51 paralogs in genome maintenance. In collaboration, we have developed a novel photo-inducible DNA ICL molecule for cancer therapy. Our work showed roles of RAD51 paralogs beyond its nuclear functions in facilitating mitochondrial DNA replication and in maintaining mitochondrial genome stability. We find that XRCC2 restrains pathological fork progression during dNTP alterations (Fig. 1). XRCC2 and XRCC3 are differentially activated by ATR kinase to protect the genome from DNA lesions and cell death. We also identified novel function of FANC-Jheli case in suppressing gene amplification.
Mycobacterium tuberculosis genome is GC rich (65%) and there are >10,000 G-rich motifs that have the potential to form G4 structures. We identified DinG as a G4 DNA resolving helicase in mycobacteria. Our work also demonstrated that M. tuberculosis RecGheli case drives efficient reversal of stalled for ks which has implications for replication restart mechanisms in M. tuberculosis.
FIG 1 : XRCC2 is required for efficient fork slowdown during nucleotide pool perturbations. (A) Representative set of DNA fibers to display fork slowing induced by HU (500 μM) in U2OS cells treated with indicated shRNAs #1 and #2 indicate two independent shRANs. (B) idU to CldU ratios of fibers from cells as shown in (A).
Homologous recombination (HR) and translesion synthesis (TLS) contribute to DNA damage tolerance in mammalian cells. However, it is unclear how the seprocesses are regulated. Currently, we are investigating whether RAD51 paralogs fine tune HR and TLS pathways to maintain integrity of the mammalian genome and supress tumorigenesis. Our preliminary studies demonstrate that FANCJ helicase controls resection of DSB ends. We wish to study the molecular mechanism by which FANCJ heli case participates in DSB repair. We also wish to understand the role of BLM and RTEL helicases in recombinational repair of DSBs and their pro- and anti-recombination functions in genome maintenance. DNA damage induced spontaneously or by exogenous our ces hampers DNA replication and, replication associated DNA lesions are the major source of genome instability that cause tumor igenesis. Cells have evolved with different pathways to deal with replication problems and there by maintain integrity of the genome. Our long term goal is to study these pathways and mechanisms in mammalian cells.In addition, studies are under progress to uncover new gene sand their mechanisms that contribute to the integrity of mammalian genome and suppress tumor igenesis.Results obtained from these studies would be used to translate this knowledge to develop novel therapeutic strategies for the treatment of genetic diseases and cancer.
Ph.D. Students 7