Understanding the basis of genome instability in nucleus and mitochondria which leads to neoplastic transformation and carcinogenesis
Summary of Research:
Title: Determining the signalling and repair pathways that are altered in human cancer
Theme of Research:
The broad aim of the research program has been to study the signaling pathways which have undergone alterations during the process of cancer development. Tumor suppressors are a group of extremely specialized proteins whose mutations lead to the development of cancer. In other words they are the caretakers and gatekeepers of our body. We are focused on the mechanisms of tumour suppressor functions. For example we ask how the tumour suppressors are activated in response to DNA damage and thereby recruited to the sites of the lesions, the mechanism of their turnover, whether and how the regulation takes place via the post-transcriptional, post-translational, epigenetic mechanisms and how these proteins counteract the functions of the oncoproteins, which are known to drive neoplastic transformation, immortalization and tumorigenesis. Finally effort in the group is also focused in determining how the tumour suppressors, either directly or indirectly, help to maintain the fidelity of the genome by regulating the different repair processes, in conjunction with other tumour suppressors or with other process-specific proteins of the different repair pathways. The focus is not only on the nuclear genome maintenance – but also on the lesser-worked mitochondrial genome, specifically on the role of mitochondrial replication in the genome maintenance process.
Our primary interest lies in an unique group of proteins called RecQ helicase family. We chose this family of helicases as three of its members, BLM, WRN and RECQL4, when mutated lead to cancer predisposition syndromes called Bloom syndrome (BS), Werner Syndrome (WS) and Rothmund-Thomson syndrome (RTS) respectively. Hence these proteins (BLM, WRN and RECQL4) can be classified as caretaker tumour suppressors. Work in the laboratory is focused on the functions of BLM and RECQL4 helicases. BLM is a nuclear helicase – which has been shown to affect multiple steps in DNA damage response and DNA repair pathways. On the other hand, the lab was the first group to show that RECQL4 is a mitochondrial helicase, which play a role in the maintenance of the mitochondrial replication. The research in the near future will focus on trying to understand the mechanisms of signal transduction during genome integrity using a combination of biochemical assays, cell culture based models involving immortalized cells obtained from patients, imaging techniques, mice models and patient tumour samples.
Ekjot Kaur, Swati Priya, Mansoor Hussain, Himanshi Agarwal, Preeti Attri, Aamir Khan, Ritu Agrawal, Swati Kulshrestha, Radhey Shyam, Nitin Kumar
• Awarded J C Bose Fellowship (2018)
• Elected Fellow of the Indian Academy of Sciences (IASc), India (2017)
• Elected Fellow of the Indian National Science Academy (INSA), India (2017)
• Elected Fellow of the National Academy of Science (NASI), India (2015)
• Elected Member of Guha Research Conference (GRC) (2011)
• Awarded National Bioscience award for Career Development, Department of Biotechnology, Government of India (2011)
• Best Thesis Award, Department of Microbiology & Cell Biology, Indian Institute of Science, Bangalore, India (1997)
- # 1. Priyadarshini R, Hussain M, Attri P, Kaur E, Tripathi V, Priya S, Dhapola P, Saha D, Madhavan V, Chowdhury S, Sengupta S (2018). BLM potentiates c-Jun degradation and alters its function as an oncogenic transcription factor. Cell Rep. 24(4):947-961. PMID: 30044990.
- # 2. TripathiV, Agarwal H, Priya S, Batra H, Modi P, Pandey M, Saha D, Raghavan SC, Sengupta S (2018). MRN complex-dependent recruitment of ubiquitylated BLM helicase to DSBs negatively regulates DNA repair pathways. Nat Commun. 9(1):1016. PMID: 29523790.
- 3. Sreekanth V, Medatwal N, Kumar S, Pal S, Vamshikrishna M, Kar A, Bhargava P, Naaz A, Kumar N, Sengupta S, Bajaj A (2017). Tethering of Chemotherapeutic Drug/Imaging Agent to Bile Acid-Phospholipid Increases the Efficacy and Bioavailability with Reduced Hepatotoxicity. Bioconjug Chem. 28(12):2942-2953. PMID: 29083862.
- 4. Sreekanth V, Medatwal N, Pal S, Kumar S, Sengupta S, Bajaj A (2017). Molecular Self-Assembly of Bile Acid-Phospholipids Controls the Delivery of Doxorubicin and Mice Survivability. Mol Pharm. 14(8):2649-2659. PMID: 28665132.
- # 5. Kumari J, Hussain M, De S, Chandra S, Modi P, Tikoo S, Singh A, Sagar C, Sepuri NB, Sengupta S (2016). Mitochondrial functions of RECQL4 are required for the prevention of aerobic glycolysis dependent cell invasion. J Cell Sci. 129(Pt 7): 1312-18. PMID: 26906415
- # 6. Kharat SS, Tripathi V, Damodaran AP, Priyadarshini R, Chandra S, Tikoo S, Nandhakumar R, Srivastava V, Priya S, Hussain M, Kaur S, Fishman JB, Sengupta S (2016). Mitotic phosphorylation of Bloom helicase at Thr182 is required for its proteasomal degradation and maintenance of chromosomal stability. Oncogene 35(8): 1025-38. PMID: 26028025
- 7. Singh M,Bansal S, Kundu S,Bhargava P,Singh A,Motiani RK,Shyam R,Sreekanth V, Sengupta S, Bajaj A (2015).Synthesis, structure-activity relationship, and mechanistic investigation of lithocholic acid amphiphiles for colon cancer therapy. Med. Chem. Commun., 6: 192-201. PMID: 25685308
- # 8. Singh M, Kundu S,Reddy MA, Sreekanth V,Motiani RK, Sengupta S*,Srivastava A*, Bajaj A* (2014). Injectable small molecule hydrogel as a potential nanocarrier for localized and sustained in vivo delivery of doxorubicin. Nanoscale 6(21): 12849-55 (* denotes co-corresponding authors). PMID: 25227567
- 9. Rajanala K, Sarkar A, Jhingan GD, Priyadarshini R, Jalan M, Sengupta S, Nandicoori VK (2014). Phosphorylation of nucleoporin Tpr governs its differential localization and is required for its mitotic functions. J Cell Sci. 127(Pt 16): 3505-20. PMID: 24938596
- # 10. Gupta S, De S, Srivastava V, Hussain M, Kumari J, Muniyappa K, Sengupta S (2014) RECQL4 and p53 potentiate the activity of polymerase and maintain the integrity of the human mitochondrial genome. Carcinogenesis 35(1): 34-45. PMID: 24067899
- 11. Sreekanth V, Bansal S,Motiani RK,Kundu S,Muppu SK, Majumdar TD, Panjamurthy S,Sengupta S,Bajaj A (2013) Design, Synthesis, and Mechanistic Investigations of Bile acid-Tamoxifen Conjugates for Breast Cancer Therapy. Bioconjug Chem. 24(9): 1468-1484. PMID: 23909664
- # 12. Chandra S, Priyadarshini R, Madhavan V, Tikoo S, Hussain M, Mudgal R, Modi P, Srivastava V, Sengupta S (2013) Enhancement of c-Myc degradation by BLM helicase leads to delayed tumor initiation. J Cell Sci. 126(Pt 16): 3782-3795. PMID: 23750012
- # 13. Tikoo S, Madhavan V, Hussain M, Miller ES, Arora P, ZlatanouA, ModiP, TownsendK, StewartGS*, Sengupta S* (2013) Ubiquitin-dependent recruitment of the Bloom Syndrome helicase in response to replication stress is required to suppress homologous recombination. EMBO J. 32(12): 1778-1792 (* denotes co-corresponding authors). PMID: 23708797
- 14. Jadav RS, Chanduri MV, Sengupta S, Bhandari R (2013) Inositol Pyrophosphate Synthesis by Inositol Hexakisphosphate Kinase I is Required for Homologous Recombination Repair. J Biol Chem. 288(5): 3312-3321. PMID: 23255604
- 15. Kumar A, Tikoo S, Maity S, Sengupta S, Sengupta S, Kaur A, Bachhawat AK (2012) Mammalian proapoptotic factor ChaC1 and its homologues function as γ-glutamyl cyclotransferases acting specifically on glutathione. EMBO Rep. 13(12): 1095-1101. PMID: 23070364
- # 16. De S, Kumari J, Mudgal R, Modi P, Gupta S, Futami K, Goto H, Lindor NM, Furuichi Y, Mohanty D, Sengupta S (2012) RECQL4 is essential for the transport of p53 to mitochondria in normal human cells in the absence of exogenous stress. J Cell Sci. 125(Pt 10): 2509-2522. PMID: 22357944
- # 17. Tikoo S, Sengupta S (2010). Time to Bloom. Genome Integr. 1(1): 14. PMID: 21050475
- # 18. Kaur S, Modi P, Srivastava V, Mudgal R, Tikoo S, Arora P, Mohanty D, Sengupta S (2010) Chk1-dependent constitutive phosphorylation of BLM helicase at Serine 646 decreases after DNA damage. Mol Cancer Res. 8(9): 1234-1247. PMID: 20719863
- 19. Larrieu D, Ythier D, Binet R, Brambilla C, Brambilla E, Sengupta S, Pedeux R (2009) ING2 controls DNA replication forks progression to maintain genome stability. EMBO Rep. 10(10): 1168-1174. PMID: 19730436
- 20. Mehta S, Miklos I, Sipiczki M, Sengupta S, Sharma N (2009) The Med8 mediator subunit interacts with the Rpb4 subunit of RNA polymerase II and Ace2 transcriptional activator in Schizosaccharomyces pombe. FEBS Lett. 583(19): 3115-3120. PMID: 19720063
- # 21. Srivastava V, Modi P, Tripathi V, Mudgal R, De S, Sengupta S (2009) BLM helicase stimulates the ATPase and chromatin remodeling activities of RAD54. J Cell Sci. 122(Pt 17): 3093-3103. PMID: 19671661
- # 22. Tripathi V, Kaur S, Sengupta S (2008) Phosphorylation-dependent interactions of BLM and 53BP1 are required for their anti-recombinogenic roles during homologous recombination. Carcinogenesis 29(1): 52-61. PMID: 17984114
- # 23. Tripathi V, Nagarjuna T, Sengupta S (2007) BLM helicase-dependent and independent roles of 53BP1 during replication stress mediated homologous recombination. J. Cell Biol. 178(1): 9-14. PMID: 17591918
# indicates papers as corresponding author
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