Indian Institute of Chemical Biology, Kolkata
Indian Association for the Cultivation of Science, Kolkata
Associate Professor at Indian Association for the Cultivation of Science, Kolkata
Genomic instability leads to cancer, premature aging and neurodegeneration. To avoid the deleterious consequences of DNA damage accumulation, cells have developed DNA damage response (DDR) pathways. In recent years it has become apparent that the cellular DDR is a rich signaling network. In addition to DNA repair per se, this network activates cell cycle checkpoints and modulates numerous cellular processes while the damage is being repaired. DNA damage induces post-translational modifications (PTMs i.e. phosphorylation, acetylation, methylation, poly(ADP)ribosylation, ubiquitylation and SUMOylation) of histones and non-histone proteins to coordinate chromatin organization and genome maintenance. DNA damaging anti-cancer agents constitutes the backbone of treatment for most solid and hematological tumors; exemplified by PARP inhibitors which generate considerable interest as single agent for tumors defective in homologous recombination (HR) such as BRCA1 or BRCA2 mutation or in combination with DNA alkylating agents (temozolomide), DNA cross-linker (cisplatin) or Topoisomerase 1 (Top1) inhibitors (camptothecin [CPT], irinotecan and topotecan).
My research is centre on evaluating the molecular basis of DNA damage and repair pathways in the nuclear and mitochondrial genome. My laboratory primarily focuses on Top1, which is essential in higher eukaryotes as it relaxes positive DNA supercoiling in advance of replication forks and transcription complexes as well as negative supercoiling behind such complexes. However, when Top1 are trapped leading to stable DNA-Top1 covalent complexes (Top1cc), the normally transient single-strand breaks evolve into double-strand breaks (DSBs), which are detrimental to the cell and ultimately lead to cell death. Our group at IACS is interested to identify new genes and novel post-translational modifications that coordinate the Top1-induced DSBs repair in cells, which can eventually pave the pathway into therapeutic benefit. We are also interested to better understand the role of mitochondrial dysfunction in human diseases.
After qualifying National Eligibility test in 2001, I landed up in Dr. Hemanta K Majumdar’s laboratory at Indian Institute of Chemical Biology, Kolkata to pursue my research career. Dr. Majumdar is an eminent molecular biologist and his laboratory has been engaged for several years in understanding the role of DNA topoisomerases from the parasitic protozoa Leishmania donovani. During my productive tenure at IICB, I cloned and characterized the novel bi-subunit topoisomerase I from the parasite Leishmania donovani and made seminal contributions in understanding the unusual structure of the parasite enzyme, their evolutionary significance and the mechanism of programmed cell death in the unicellular parasite induced by topoisomerase I specific inhibitors. The importance of my doctoral research is highlighted in several peer reviewed journals including JBC, Nucleic Acids Research, Cancer Research, FEBS Letters, Cell Death Differentiation, Biochem J, Molecular Pharmacology etc. My doctoral research was summarized in a review article “Topoisomerases of kinetoplastid parasites: why so fascinating?” Das et al., 2006. Molecular Microbiology.
Then, I moved to Dr. Yves Pommier’s laboratory at National Cancer Institute /NIH/USA for postdoctoral studies. Dr. Pommier is a pioneer in small molecule inhibitors for topoisomerase; DNA damage induced signaling pathways and regulation of gene expressions. At NCI, I continued my research on DNA topoisomerase I by focusing on the human enzyme, and more specifically on the newly discovered enzyme, tyrosyl-DNA-phophodiesterase (TDP1), and its role in repair of topoisomerase I-induced DNA damage in cancer. My postdoctoral research helped to unravel the novel regulation of human TDP1 by the DNA damage response (DDR) pathways involving Ataxia Telangiectasia mutated (ATM) and DNA-dependent protein kinase (DNA-PK) (EMBO journal, 2009). Later my work also discovered that TDP1 (nuclear encoded gene) is imported to mitochondria for repairing mitochondrial DNA damage (PNAS, 2010). The impact of this discovery is very high because mitochondrial DNA is currently the focus of many investigations for several neurological diseases. Moreover, homozygous mutation of TDP1 causes spinocerebellar ataxia with axonal neuropathy (SCAN1), a severe neurodegenerative syndrome.
Our recent work at Indian Association for the Cultivation of Science (IACS), identifies poly(ADP)ribose polymerases (PARP1) as a key component of the TDP1 repair pathway for Top1cc repair and provides the molecular mechanism explaining the synergism between PARP and Top1 inhibitors, which is highly relevant for the ongoing clinical trials (Nucleic Acids Research, 2014). PARP1 are DNA nick sensors and have been proposed to play a critical role in the early detection and repair of Top1cc-induced DNA breaks. We recently describe a novel role for PAR polymers on the regulation of Top1 nuclear dynamics. Using a combination of live cell microscopy and fluorescence recovery after photobleaching (FRAP) kinetic modeling, we establish that orally bioactive PARP inhibitors (Veliparib, ABT-888) efflux Top1 from the nucleolus to the nucleoplasm. We show combination of ABT-888 with CPT treatment markedly increased the Top1-suicidal complexes (Top1cc) across the nuclear genome, which is associated with increased cytotoxicity in the proliferating cells exposed to the combination of PARP inhibitor with Top1 inhibitor. Thus, this study provides rationale for the combination of PARP inhibitors with Top1 inhibitors in cancer treatment (particularly BRCA1 and 2 deficient breast and ovarian cancer) (Nucleic Acids Research, 2016). The above findings have opened an entire new avenue for studying the fundamental mechanism by which targeting DNA repair pathways could enhance the therapeutic benefits of Top1 poisons in cancer.
For outstanding research and contribution to the scientific community, I was awarded the prestigious NIH Fellows Award for Research Excellence for two consecutive years (2009 and 2010) selected in top five postdoctoral fellows at NCI (2012). I was also invited by pioneers in the field of DNA repair to present my work at several meetings including the Research Forum at the Lombardi Comprehensive Cancer Center of Georgetown University Medical Center, Washington DC, in 2009, the NDDO Honorary Award Lecture session, 8th International Symposium on Targeted Anticancer Therapies in 2010 at Washington DC, USA, the Cold Spring Harbor meeting, in 2011, and the Gordon Conference 2012 and 2013, USA. In 2013, I was selected for the prestigious Wellcome Trust-DBT India Alliance Intermediate fellowship, the Ramalingaswami Fellowship (Department of Biotechnology, India) and Ramanujan Fellowship (Department of Science and Technology, India) for starting my independent research group in India.
In December 2012, I started my independent research group as an Assistant Professor at the Indian Association for the Cultivation of Science (IACS), Kolkata. IACS is the oldest and one of the premier research institutes in India dedicated to foster the basic science research in the frontier areas of Chemistry, Biology and Physics. The Director, IACS have been very supportive in my endeavors and the Wellcome Trust/India alliance Intermediate Fellowship played a pivotal role in building up a state-of-the-art research facility to conduct high-impact research in my laboratory. Finally my parents, wife and my daughter are my primary inspiration for my work.