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सागर सेनगुप्ता

Research Interest:

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 during genomic instability in nucleus and mitochondria

Theme of Research:

A. Development of therapeutics against colon cancer detection:
Colon cancer is one of the most common type of cancer in India. A major issue for colon cancer treatment is the recurrence. Recurrence occur due to the development of chemoresistance to the drugs used to treat the primary colon cancer. Using a unbiased screening procedure and multiple mice models we have identified three small molecules (which are FDA) we have identified three molecules which can act to prevent chemoresistance and allow the chemotherapeutic drugs like cisplatin, camptothecin and oxaliplatin to optimally function (Kaur et al., Journal of Clinical Investigation, 2024). Efforts are being made to use these small molecules for adjunct therapy in cancer treatments.

There is a unmet need of colon cancerdetection methods, especially in the early stages. We discovered six microRNAs (which were named DNA 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 patients from AIIMS, New Delhi indicated found that the DDSMs were all upregulated even in Stage I coloncancer tissues and not in the surrounding normal tissues(Priya et al., Journal of Cell Science, 2021). This microRNA based signature is being taken forward as a potential biomarker for coloncancer detection.

B. Determine how tumor suppressors recognize the damaged DNA: 
Human cells are exposed to multitude of DNA damage every day. Our work has tried to understand how DNA damage was recognized by the cells so that it could be repaired by either of the two main repair pathways – homologous recombination and non-homologous end joining. We showed that cells have overlapping yet distinct processes to recognize different types of DNA damages. Ubiquitylation of tumour 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 some of the key determinants of this process (Tikoo et al., The EMBO Journal, 2013; Tripathi et al., Nature Communications, 2018).

C. Understanding the role of tumor suppressors in the repair of damaged DNA:
Our work had provided evidence that a phosphorylation-dependent interaction between several key proteins involved in the repair pathway allows cells to repair the damaged DNA by homologous recombination (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 factors which would repair the damaged genome (Srivastava et al., Journal of Cell Science, 2009).

D. Dissecting the role of protein turnover during cancer development:
We have tried to understand the inter-regulation between the tumour suppressors and the E3 ligases during cancer development. We have demonstrated how a well-known E3 ligase in colon cancer development, called Fbw7a, is allowed to optimally recognize its oncogenic substrates like the oncoproteins c-Myc and c-Jun (Chandra et al., Journal of Cell Science, 2012; Priyadarshini et al., Cell Reports, 2018). Further also determined the mechanism degradation of two tumour suppressors by Fbw7a, 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).

E. Identifying and characterizing the functions of a new mitochondrial helicase:
Apart from the nucleus, mitochondria have its own genetic material. We identified a new mitochondrial helicase, RECQL4. We identified how this helicase goes to the mitochondria, interacts with different mitochondrial proteins and affects the mitochondrial replication process (De et al., Journal of Cell Science, 2012). Further we provided mechanistic evidence how RECQL4 enhanced the functions of the sole mitochondrial polymerase, Pol
gA (Gupta et al., Carcinogenesis, 2014). Lack of such a functional interaction led to more accumulation of DNA damage in mitochondrial DNA which contributed to the initiation of cancer (Kumari et al., Journal of Cell Science, 2016).

Group Members:
In BRIC-NII: Ritu Agrawal, Aftab Mohammed, RimpyArun, Savita, Tavleen Kaur
In BRIC-NIBMG: Sadananda Kumbhakar, Hanif Ahmed
Junior Research Fellow - In BRIC-NII:Vandana Sharma
Technical Assistant - In BRIC-NII: Chetana Mukherjee

Awards:
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)
8. 2018 - J C Bose Fellowship
9. 2021 - Professor Vishwa Nath Memorial Award Lecture by INSA
10. 2022 - Elected Vice President of Indian Association of Cancer Research
11. 2023 - GK Manna Memorial Award Lecture by All India Congress of Genetics and Genomics
12. 2023 - Lalji Singh Memorial Award Lecture by the Society for Mitochondrial Research & Medicine
13. 2024 - J C Bose Fellowship (2nd term)

Collaborators:
Arnab Mukhopadhyay (National Institute of Immunology, New Delhi, India)
Avinash Bajaj (Regional Centre for Biotechnology, Faridabad, India)
Patrick Legembre (Universite de Rennes, Rennes, France)
SamudralaGourinath (Jawaharlal Nehru University, New Delhi, India)
RituKulshreshtha (Indian Institute of Technology Delhi, New Delhi, India)

Publications:
  • Yadav P, Rana K, Nardini V, Khan A, Pani T, Kar A, Jain D, Chakraborty R, Singh R, Jha SK, Mehta D, Sharma H, Sharma RD, Deo SVS, Sengupta S, Patil VS, Faccioli LH, Dasgupta U, Bajaj A (2024). Engineered Nanomicelles inhibit the tumour progression via abrogating the prostaglandin-mediated immunosuppression. J Control Release.368:548-565.  PMID: 38462044
  • # Kaur E, Agrawal R, Arun R, Madhavan V, Srivastava V, Kumar D, Rath PP, Kumar N, Vedagopuram S, Pandey N, Priya S, Legembre P, Gourinath S, Bajaj A, Sengupta S (2024). Small molecules that disrupt RAD54-BLM interaction hamper tumor proliferation in colon cancer chemoresistance models. J Clin Invest. 134(8):e161941. PMID: 38421735
  • # Hussain M, Mohammed A, Saifi S, Priya S, Sengupta S (2023). Hyper-ubiquitylation of DNA helicase RECQL4 by E3 ligase MITOL prevents mitochondrial entry and potentiates mitophagy. J. Biol Chem. 299(9):105087. PMID: 37495109
  • Kar A, Jain D,Kumar S,Rajput K,Pal S,Rana K,Kar R,Jha SK, Medatwal N,Yavvari PS,Pandey N,Mehta D,Sharma H,Bhattacharya D,Pradhan MK,Sharma RD,Srivastava A,Agrawal U,Mukhopadhyay A,Sengupta S,Patil VS,Bajaj A, Dasgupta U (2023). A localized hydrogel-mediated chemotherapy causes immunogenic cell death via activation of ceramide-mediated unfolded protein response. Sci Adv. 9(26): eadf2746. PMID: 37390205
  • Mondal I, Fatima SW, Priya S, Sengupta S, Khare SK, Kulshreshtha R (2023). Transglutaminase-Polyethyleneimine Nanoflowers Mediated Cellular Delivery of Anti-miR-210 for Effective Glioblastoma Therapy. ACS Biomater Sci Eng. 9(5): 2558-2571. PMID: 37067339
  • # Hussain M, Saifi S, Mohammed A, Sengupta S (2022). Protocol to detect in vitro and in cell ubiquitylation of mitochondrial DNA polymerase gamma by mitochondrial E3 ligase MITOL. STAR Protoc. 3(4):101710. PMID: 36136752
  • # Priya S, Kaur E, Kulshrestha S, Pandit A, Gross I, Kumar N, Agarwal H, Khan A, Shyam R, Bhagat P, Prabhu JS, Nagarajan P, Deo SVS, Bajaj A, Freund JN, Mukhopadhyay A, Sengupta S (2021). CDX2 inducible microRNAs sustain colon cancer by targeting multiple DNA damage response pathway factors. J Cell Sci. 134(15): jcs258601. PMID: 34369561
  • Sreekanth V, Pal S, Kumar S, Komalla V, Yadav P, Shyam R, Sengupta S, Bajaj A (2021). Self-assembled supramolecular nanomicelles from bile acid-docetaxel conjugate are highly tolerable with improved therapeutic efficacy. Biomater Sci. 9(16): 5626-5639. PMID: 34254078
  • # Kaur E, Agrawal R, Sengupta S (2021). Functions of BLM helicase in cells: is it acting like a double-edged sword? Front Genet. 12:634789. PMID: 33777104
  • # Hussain M, Mohammed A, Saifi S, Khan A, Kaur E, Priya S, Agarwal H, Sengupta S (2021). MITOL-dependent ubiquitylation negatively regulates the entry of PolA into mitochondria. PLoS Biol. 19(3): e3001139. PMID: 33657094
  • Sreekanth V, Kar A, Kumar S, Pal S, Yadav P, Sharma Y, Komalla V, Sharma H, Shyam R, Sharma RD, Mukhopadhyay A, Sengupta S, Dasgupta U, Bajaj A. (2021). Bile acid tethered Docetaxel-based nanomicelles mitigate tumor progression through epigenetic changes. AngewChemInt Ed Engl. 60(10): 5394-5399. PMID: 33258265
  • Rajarajan S, Anupama CE, Jose B, Correa M, Sengupta S, Prabhu JS (2020). Identification of colorectal cancers with defective DNA damage repair by immuno histochemical profiling of mismatch repair proteins, CDX2 and BRCA1. MolClin Oncol. 13(5): 57. PMID: 32953111
  •  Lochab S, Singh Y, Sengupta S, Nandicoori VK (2020). Mycobacterium tuberculosis exploits host ATM kinase for survival advantage through SecA2 secretome. Elife. 9: e51466. PMID: 32223892
  • 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 tumor progression through alteration of sphingolipid metabolism. ACS Cent Sci. 5: 1648-1662. PMID: 31660434.
  •  # Tripathi V, Kaur E, Kharat SS, Hussain M, Damodaran AP, Kulshrestha S, Sengupta S (2019). Abrogation of FBW7α-dependent p53 degradation enhances p53’s function as a tumor suppressor. J Biol Chem. 294(36):13224-13232. PMID: 31346036.

 

#  indicates papers as corresponding author

Complete List of Publications : https://www.ncbi.nlm.nih.gov/myncbi/1t7wpVLc8yt/bibliography/public/

Faculties

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