Department of Genetics, Cell Biology and Anatomy
MS 1992 University of Calcutta, India
Ph.D. 1999 Indian Institute of Chemical Biology
Postdoc. 2001 University of Texas Medical Branch, USA
Co-Course Director, IPBS 802 Molecular Cell Biology
Co-Course Director, MGCB 903 Journal Club
Co-Course director MGCB 912 Modern Approaches in Cell Biology and Molecular Genetics
Tumor recurrence and metastasis remain the major clinical challenges for cancer treatment. Ionizing radiation (IR) and chemotherapies have been the first line of care for treatment of many types of cancers including brain and pancreatic cancer. These conventional cytotoxic therapies cause DNA damage and induce cell death. Although this standard of care has significantly improved the overall survival rates, high doses of chemo and IR are associated with long-term toxicities in surviving patients. Moreover, postsurgical residual tumor in some groups of patients rapidly develop therapy-resistant which often leads to tumor recurrence and distal metastasis. The major goals of our lab are to understand the molecular mechanisms that alter the damage repair pathways and gene expression in tumor cells to promote therapy resistance and tumor recurrence and develop second line of interventions to prevent tumor recurrence and metastasis and improve the quality of life of patients.
We have recently discovered a novel mechanistic connection between elevated levels of a DNA repair protein APE1, a histone chaperone FACT complex and G-quadruplex (G4), a non-canonical (non-B form) four-stranded DNA secondary structure in promoting therapy-induced damage repair and gene expression. Our research goals are to elucidate how these factors work together to promote resistance to radiation and chemo and develop targeted multifunctional nanoparticles (NP) loaded with chemo or radiosensitizers to target therapy resistance tumor cells and prevent tumor recurrence and metastasis in a preclinical model.
Triple-negative breast cancer (TNBC) is the most aggressive breast cancer (BC) among all the BC subtypes due to its exceptionally high metastasis rate. TNBC patients with metastasis have a short overall survival as the endocrine therapy and chemotherapy are inefficient in TNBC treatment. Studies have revealed that G4 DNA is highly enriched in TNBC signature genes’ promoters, and our lab was the first one to uncover that DNA repair protein APE1 binds to G4 and regulates its stability in cells. We are interested in elucidating the interaction between APE1 and G4 in TNBC and their roles in regulating TNBC metastasis and targeting APE1-G4 interaction as a potential therapeutic approach to inhibit TNBC metastasis.
Our collaborative multidisciplinary approaches use cutting edge genetic and molecular tools and drug delivery systems to understand therapy resistance and metastasis. We are looking for talented students and postdocs. who get the opportunity to develop innovative ideas in individualized project.
- Pramanik S, Chen Y, Song H, Khutsishvili I, Marky LA, Ray S, Natarajan A, Singh PK, Bhakat KK. The Human AP-endonuclease 1 (APE1) is a DNA G-quadruplex Structure Binding Protein and Regulates KRAS Expression in Pancreatic Ductal Adenocarcinoma Cells. Nucleic Acids Res. (2022),50:3394-3412. PMCID: PMC8990529 DOI: 1093/nar/gkac172
- Song, H., Xi, , Chen, Y., Pramanik, S., Zeng, J , Roychoudhury , S., Harris , H., Akbar , A., Elhag , S., Coulter , D., Ray , S., Bhakat, KK.. Histone chaperone FACT complex inhibitor CBL0137 interferes with DNA damage repair and enhances sensitivity of medulloblastoma to chemotherapy and radiation. Cancer Lett. (2021), 520:201-212. PMCID: PMC8440470 DOI: 10.1016/j.canlet.2021.07.020
- Pramanik S, Roychoudhury S and Bhakat KK. Oxidized DNA base damage repair and transcription: a new mechanism for regulation of gene expression in cancer. Handbook of Oxidative stress and Cancer, Springer Nature (2022).
- Bhakat KK. and Ray S. The FAcilitates Chromatin Transcription (FACT) complex: Its roles in DNA repair and implications for cancer therapy. DNA Repair, (2022), 109: doi: 10.1016/j.dnarep.2021.103246.
- Roychoudhury S, Pramanik S, Harris H, Tarpley M, Sarkar A, Spagnol G, Sorgen P, Chowdhury D, Band V, Klinkebiel D, Bhakat KK. Endogenous oxidized DNA bases and APE1 regulate the formation of G-quadruplex structures in the genome. Proceedings of National Academy of Sciences, USA (2020), 117: (21) 11409-11420. PMCID: PMC7260947 DOI: 1073/pnas.1912355117
- Ray S, Chaturvedi NK, Bhakat KK., Rizzino A, Mahapatra S. Subgroup-Specific Diagnostic, Prognostic, and Predictive Markers Influencing Pediatric Medulloblastoma Treatment. Diagnostics (Basel), (2021), 12 (1) 61. doi: 10.3390/diagnostics12010061.
- Song H, Zeng J, Roychoudhury S, Biswas P, Mohapatra B, Ray S, Dowlatshahi K, Wang J, Band V, Talmon G, Bhakat KK. Targeting Histone Chaperone FACT Complex Overcomes 5-Fluorouracil Resistance in Colon Cancer. Mol Cancer Ther. (2020) 19:258-269.
- Roychoudhury S, Nath S, Song H, Hegde ML, Bellot LJ, Mantha AK, Sengupta S, Ray S, Natarajan A, Bhakat KK. Human Apurinic/Apyrimidinic Endonuclease (APE1) Is Acetylated at DNA Damage Sites in Chromatin, and Acetylation Modulates Its DNA Repair Activity. Mol Cell Biol. (2017) 37(6). PMCID: PMC5335514 DOI: 1128/MCB.00401-16
- Nath S, Roychoudhury S, Kling MJ, Song H, Biswas P, Shukla A, Band H, Joshi S, Bhakat KK. The extracellular role of DNA damage repair protein APE1 in regulation of IL-6 expression..Cell Signal. (2017) Nov;39:18-31. PMID:28751279
- Sengupta S, Mantha AK, Song H, Roychoudhury S, Nath S, Ray S, Bhakat KK. Elevated level of acetylation of APE1 in tumor cells modulates DNA damage repair. 2016;7(46):75197-209.