Understanding the mechanisms of genome integrity in nucleus and mitochondria
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 cancer detection 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 colon cancer 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 colon cancer 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 proteins and 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 chromatin organization 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).
E. 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 byFbw7a, thereby allowing the potential development of a non-degradable versions which can resist turnover and thereby be active for a longer duration (Kharat et al., Oncogene, 2016; Tripathi et al., Journal of Biological Chemistry, 2019).
F. 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, PolgA (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).
G. Understanding the mechanism of the entry of proteins into mitochondria:
For long time mitochondrial protein entry was thought to be dependent only on the presence or absence of mitochondrial localization signal (MLS). We recently provided evidence that apart from MLS, there existed another mechanism for mitochondrial entry. Ubiquitylation of two proteins involved in mitochondrial replication, PolgA and RECQL4, by a specific E3 ligase(called MITOL) on the outer surface of the organelle prevented their entry. This post-translational modification which allowed only the non-ubiquitylated PolgA and RECQL4 to enter the organelle. We demonstrated this phenomenon contributed to the mitochondrial disorders, namely autosomal dominant progressive external ophthalmoplegia (adPEO) and Rothmund Thomson Syndrome (RTS). Manipulation of the ubiquitylation status of PolgA and RECQL4 mutants reverted the process allowing the functional reactivation of these proteins (Hussain et al., PLoS Biology, 2021)
| 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
2012-2018 & 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
2022 Member of Expert Committee meeting for CSIR Mission-IndigenMed
2023 Member of the Scientific Advisory Board of Advanced Research Unit on Metabolism, Development & Aging (ARUMDA)
2023-2024 Member of Monitoring Committee for CSIR-MLP project om T cell immune monitoring for Covid-19
2023 Member of the screening committee for DBT Research Resources, Service Facilities and Platforms (RRSEP)
2023 Member of DBT Sectorial Expert Committee on Biomanufacturing
2023 Member of CII National Task Force on Science and Data (Genomics)
2023 Member of National Cancer Innovation Leadership Initiative [NCiLi]
| 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) |
| 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) |
1. Grant agency: Council of Scientific and Industrial Research (CSIR), India
Role: PI
Title of the project and Reference number: Determine the mechanism of the turnover of the key mitochondrial helicase, RECQL4, inside the organelle (27/0387/23/EMR-II)
Period of support: 01.12.2023 to 30.11.2026
Total amount of support: Rs. 27.74 lakhs
2. Grant agency: Indo-French Centre for Promotion of Advanced Research (IFCPAR/CEFIPRA)
Role: PI
Title of the project and Reference number: Identify, characterize and determine the in vivo efficacy of small molecules using a synthetic lethality screen which targets the major DNA repair pathways in colon and lung cancer (IFC/6803-1/2022)
Period of support: 01.11.2023 to 30.10.2026
Total amount of support: Rs. 83.49 lakhs
3. Grant agency: Department of Biotechnology (DBT), India
Role: PI
Title of the project and Reference number: Determining the mechanism and consequences of inter-regulation between two tumor suppressors: p53 and BLM helicase (BT/PR41739/BRB/10/1974/2021)
Period of support: 18.10.2022 to 17.10.2025
Total amount of support: Rs. 91.837 lakhs
4. Grant agency: Board of Research in Nuclear Sciences (BRNS), India
Role: PI
Title of the project and Reference number: Understanding the mechanism by which BLM helicase regulates ATM mediated response to ionizing irradiation (58/14/17/2021-BRNS)
Period of support: 30.11.2021 to 29.11.2024
Total amount of support: Rs. 42.136 lakhs
5. Grant agency: Science and Engineering Research Board (SERB), India
Role: PI
Title of the project and Reference number: Determine whether mitochondrial helicase RECQL4 affects SIRT3 activity by regulating OXPHOS Complex I stability and assembly (CRG/2020/000125)
Period of support: 21.01.2022 to 20.01.2025
Total amount of support: Rs. 71.25 lakhs
Personal URL:
https://www.ncbi.nlm.nih.gov/myncbi/1t7wpVLc8yt/bibliography/public/
# Indicates publications as corresponding author
1. 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
# 2. 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
# 3. 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
4. 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
5. 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
# 6. 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
# 7. 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
8. 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
# 9. 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
# 10. 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 PolgA into mitochondria. PLoS Biol. 19(3): e3001139. PMID: 33657094
11. 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. Angew Chem Int Ed Engl. 60(10): 5394-5399. PMID: 33258265
12. Rajarajan S, Anupama CE, Jose B, Correa M, Sengupta S, Prabhu JS (2020). Identification of colorectal cancers with defective DNA damage repair by immunohistochemical profiling of mismatch repair proteins, CDX2 and BRCA1. Mol Clin Oncol. 13(5): 57. PMID: 32953111
13. 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
14. 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.
# 15. 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.
