Understanding the mechanisms of genome integrity in nucleus and mitochondria
Human cells are exposed to multitude of DNA damage every day. Our work wanted to understand howDNA damage was recognized by the cells so that it could be repaired by either of the two main repairpathways – homologous recombination and non-homologous end joining. We showed that cells haveoverlapping yet distinct processes to recognize different types of DNA damages. Ubiquitylation oftumour suppressor BLM by chromatin associated E3 ligases, interactions with process specific proteinsand a biphasic mode of recruitment to the site of damage which was dependent on cell cycle – were someof the key determinants of this process (Tikoo et al., The EMBO Journal, 2013; Tripathi et al., NatureCommunications, 2018).
Our work had provided evidence that a phosphorylation-dependent interaction between several keyproteins involved in the repair pathway allows cells to repair the damaged DNA by homologousrecombination (Tripathi et al., Journal of Cell Biology, 2007; Carcinogenesis, 2008; Kaur et al.,Molecular Cancer Research, 2010). Subsequently we have provided evidence how the chromatinorganization is acted upon by chromatin remodelers in cells to allow better accessibility of the factorswhich would repair the damaged genome (Srivastava et al., Journal of Cell Science, 2009).
We have tried to understand the inter-regulation between the tumour suppressors and the E3 ligasesduring cancer development. We have demonstrated how a well-known E3 ligase in colon cancerdevelopment, called Fbw7, is allowed to optimally recognize its oncogenic substrates like theoncoproteins c-Myc and c-Jun (Chandra et al., Journal of Cell Science, 2012; Priyadarshini et al., CellReports, 2018). Further also determined the mechanism degradation of two tumour suppressors byFbw7, thereby allowing the potential development of a non-degradable versions which can resistturnover and thereby be active for a longer duration (Kharat et al., Oncogene, 2016; Tripathi et al.,Journal of Biological Chemistry, 2019).
Colon cancer is the third most common type of cancer in India. Hence there is a unmet need of cancerdetection methods, especially in the early stages. We discovered six microRNAs (which were namedDNA damage sensitive microRNAs or DDSMs) which were upregulated only in colon cancer cells.Analysis done with more than 410 patient information in TCGA and the biopsy materials of 54 patientsfrom AIIMS, New Delhi indicated found that the DDSMs were all upregulated even in Stage I coloncancer tissues and not in the surrounding normal tissues. More importantly increased expression of theDDSMs in the cancer patients decreased the probability of their survival (Priya et al., Journal of CellScience, 2021). This microRNA based signature is being taken forward as a potential biomarker for coloncancer detection.
Apart from the nucleus, mitochondria have its own genetic material. We identified a new mitochondrialhelicase, RECQL4. We identified how this helicase goes to the mitochondria, interacts with differentmitochondrial proteins and affects the mitochondrial replication process (De et al., Journal of CellScience, 2012). Further we provided mechanistic evidence how RECQL4 enhanced the functions of thesole mitochondrial polymerase, PolA (Gupta et al., Carcinogenesis, 2014). Lack of such a functionalinteraction led to more accumulation of DNA damage in mitochondrial DNA which contributed to theinitiation of cancer (Kumari et al., Journal of Cell Science, 2016).
|S. No.||Degree||Board/University||Division||Year of Passing||Subjects|
|1||B. Sc.||University of Calcutta||Second||1988||Chemistry (Honours), Physics, Mathematics|
|2||M. Sc.||University of Calcutta||First (Silver medalist)||1991||Biochemistry|
|3||Ph.D.||Indian Institute of Science||Best thesis award||1997||Microbiology and Cell Biology|
|S. No.||From||To||Name of organization||Position held||Subject area|
|1||07/1996||01/2001||Institut de Genetique et de Biologie Moleculaire et Cellulaire (IGBMC), Strasbourg, France||Post-doctoral Fellow||Cancer Biology|
|2||01/2001||09/2004||National Cancer Institute, National Institutes of Health, Bethesda, USA||Visiting Fellow||Cancer Biology|
2012-2013 Member of DBT North Eastern Region Twining Program Task Force
2016-2017 Member of DBT Expert Committee on promotion and Popularization of Biotechnology
2017 Special invitee in SERB Health Science Program Advisory Committee (PAC)
2017 Special invitee in SERB Program Advisory Committee (PAC) for International Cooperation in the area of Life Sciences & Medical Biology
2017 Member of DBT Glue Grant Scheme
2017-2020 Member of Technology Development Board (TDB) project evaluation committee
2022-till date Member of DBT Cancer Biology Task Force
2019-till date Member of SERB Program Advisory Committee (PAC) on Interdisciplinary Biological Sciences
2020 Special invitee in “Expert Committee” for evaluation of DBT-DFG grant proposals
2020-2021 Member of evaluation committee of proposals received under DBT call on “Setting up Virtual Network Centres on Cancer Immunology and Immunotherapy”
2021 Special invitee in SERB Biophysics, Biochemistry, Molecular Biology and Microbiology Program Advisory Committee (PAC)
2021 Member of SERB-SUPRA screening committee
2021 Member of Search Cum Selection committee meeting of SERB POWER Fellowship
2021-2022 Member of SERB POWER grant committee
2022 Mentor and reviewer of Ramalingaswami Re-entry Fellowship Conclave
|S. No.||Year||Honors/ Awards/Fellowship|
|1||1991||Silver medallist in M.Sc., University of Calcutta, India.|
|2||1997||Best thesis award, Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore, India.|
|3||2011||National Bioscience award for Career Development by Department of Biotechnology, India|
|4||2011||Elected as a member of Guha Research Conference|
|5||2015||Elected Fellow of the National Academy of Science (NASI)|
|6||2017||Elected Fellow of the Indian Academy of Sciences (IASc)|
|7||2017||Elected Fellow of the Indian National Science Academy (INSA)|
|7||2018||J C Bose Fellowship|
|8||2022||Elected Vice President of Indian Association of Cancer Research|
# 1. Hussain M, SaifiS, Mohammed A, Sengupta S (2022). Protocol todetect in vitro and in cell ubiquitylation of mitochondrial DNA polymerasegamma by mitochondrial E3 ligase MITOL. STARProtoc. 3(4):101710. PMID: 36136752
# 2. Priya S, Kaur E,Kulshrestha S, Pandit A, Gross I, Kumar N, Agarwal H, Khan A, Shyam R, BhagatP, Prabhu JS, Nagarajan P, Deo SVS, Bajaj A, Freund JN, Mukhopadhyay A, Sengupta S (2021). CDX2 induciblemicroRNAs sustain colon cancer by targeting multiple DNA damage responsepathway factors. J Cell Sci. 134(15): jcs258601. PMID: 34369561
3. SreekanthV, Pal S, Kumar S, Komalla V, Yadav P, Shyam R, Sengupta S, Bajaj A (2021). Self-assembled supramolecularnanomicelles from bile acid-docetaxel conjugate are highly tolerable withimproved therapeutic efficacy. Biomater Sci. 9(16): 5626-5639. PMID: 34254078
#4. Kaur E, Agrawal R, Sengupta S (2021). Functions ofBLM helicase in cells: is it acting like a double-edged sword? Front Genet. 12:634789. PMID: 33777104
# 5. Hussain M,Mohammed A, Saifi S, Khan A, Kaur E, Priya S, Agarwal H, Sengupta S (2021). MITOL-dependent ubiquitylation negativelyregulates the entry of PolgA into mitochondria. PLoS Biol. 19(3): e3001139. PMID: 33657094
6. Sreekanth V, Kar A, Kumar S, Pal S, Yadav P,Sharma Y, Komalla V, Sharma H, Shyam R, Sharma RD, Mukhopadhyay A, SenguptaS, Dasgupta U, Bajaj A. (2021). Bile acid tethered Docetaxel-basednanomicelles mitigate tumor progression through epigenetic changes. Angew ChemInt Ed Engl. 60(10): 5394-5399.
7.Rajarajan S, Anupama CE, Jose B, Correa M, Sengupta S, Prabhu JS (2020).Identification of colorectal cancers with defective DNA damage repair byimmunohistochemical profiling of mismatch repair proteins, CDX2 and BRCA1. MolClin Oncol. 13(5): 57. PMID: 32953111
8.Lochab S, Singh Y, Sengupta S, Nandicoori VK (2020). Mycobacteriumtuberculosis exploits host ATM kinase for survival advantage throughSecA2 secretome. Elife. 9: e51466. PMID: 32223892
9. Pal S,Medatwal N, Kumar S, Kar A, Komalla V,Yavvari P, Mishra D, Rizvi Z, Nandan S, Malakar D, Pillai M, Awasthi A, Das P,Sharma R, Srivastava A, Sengupta S,Dasgupta U, Bajaj A (2019). A localized chimeric hydrogel therapy combats tumorprogression through alteration of sphingolipid metabolism. ACS Cent Sci. 5:1648-1662. PMID:31660434.
#10. Tripathi V, Kaur E, Kharat SS, Hussain M,Damodaran AP, Kulshrestha S, Sengupta S(2019). Abrogation ofFBW7α-dependent p53 degradation enhances p53’s function as a tumor suppressor.J Biol Chem. 294(36):13224-13232. PMID:31346036.
#11. Priyadarshini R, Hussain M, Attri P, Kaur E,Tripathi V, Priya S, Dhapola P, Saha D, Madhavan V, Chowdhury S, Sengupta S (2018). BLM potentiatesc-Jun degradation and alters its function as an oncogenic transcription factor.Cell Rep. 24(4):947-961. PMID: 30044990.
#12. Tripathi V, Agarwal H, Priya S,Batra H, Modi P, Pandey M, Saha D, Raghavan SC, Sengupta S (2018). MRN complex-dependent recruitment ofubiquitylated BLM helicase to DSBs negatively regulates DNA repair pathways. Nat Commun.9(1):1016. PMID: 29523790.
13.Sreekanth V, MedatwalN, Kumar S, Pal S, Vamshikrishna M, Kar A, Bhargava P, Naaz A, Kumar N, Sengupta S, Bajaj A (2017). Tetheringof Chemotherapeutic Drug/Imaging Agent to Bile Acid-Phospholipid Increases theEfficacy and Bioavailability with Reduced Hepatotoxicity. Bioconjug Chem. 28(12):2942-2953. PMID: 29083862.
14.Sreekanth V, Medatwal N,Pal S, Kumar S, Sengupta S, Bajaj A(2017). Molecular Self-Assembly of Bile Acid-Phospholipids Controls theDelivery of Doxorubicin and Mice Survivability. Mol Pharm.14(8):2649-2659. PMID: 28665132.