We are interested in the molecular basis of cell death and proliferation control during the genotoxic stress response. Our laboratory has focused on two tumor models: (i) Chronic lymphocytic leukemia (CLL) for leukemia, and (ii) prostate, for epithelial tumors. One project seeks to understand the DNA damage signals incurred by mammalian cells following ionizing radiation (IR). We are interested in IR-regulated genes, with a focus on those that have an important role in cell cycle checkpoints, cell proliferation, apoptosis (Bcl-2 family), and autophagy (ATG family, mTOR). The second project is focused on understanding how the three fundamental cellular responses to IR, cell cycle control, DNA repair, and cell death are integrated. Our recent studies have shown that Cyclin E undergoes a proteolytic, caspase-mediated cleavage during the early stages of apoptosis in hematopoietic cells. The resulting C-terminal fragment of Cyclin E, can no longer sustain cell cycle regulation as it cannot bind to its catalytic partner Cdk2. Instead, it binds to the DNA repair protein Ku70. As a result: (i) in the nucleus it impairs DNA repair by preventing recruitment of accessory proteins (e.g. DNA Ligase IV, XRCC4) to the DNA repair complex assembled on double-stranded DNA, and (ii) in the cytoplasm, it dislocates BAX from Ku70 triggering BAX activation, or when expressed chronically activates autophagy leading to senescence. The third project focuses on a tumor-specific cell death ligand, Apo2L/TRAIL and its role in apoptosis, autophagy and potential for cancer therapy.
One area of focus has been to determine the molecular basis of cell death and proliferation control during the genotoxic stress response, such as encountered during chemotherapy or radiotherapy (RT) in leukemia and prostate cancer. We have been examining the DNA damage signals incurred by mammalian cells following RT. We are interested in IR-regulated genes, with a focus on those that have an important role in apoptosis, autophagy, checkpoints, and cell cycle control. Another area of interest has been the understanding of how the three fundamental cellular responses to RT: cell cycle control, DNA repair, and cell death, are integrated.
Al-harbi S, et al. An anti-apoptotic Bcl-2 family expression index predicts the response of CLL to ABT-737. Blood, 2011; 118:3579-90.
Singh K, et al. Autophagy-dependent senescence in response to DNA damage and chronic apoptotic stress. Autophagy, 2012; 8:236-51.
Mazumder S, et al. Mcl-1 phosphorylation defines ABT-737 resistance that can be overcome by increased NOXA expression in leukemic B-cells. Cancer Res, 2012; 72:3069-3079.
Zhou N, et al. Clinical Cancer Res, 2013; 19: 1717-28.
Chatterjee P, et al. PARP inhibition radiosensitizes most effectively to low dose-rate radiation PTEN-deficient and TMPRSS2-ERG fusion gene-expressing prostate cancer cells. PloS One, 2013: 8: e60408. PMC3614551
Sharma A, et al. BECN1 and BIM interactions with MCL-1 determine fludarabine resistance in leukemic B cells. Cell Death & Disease, 2013; L4: e628. PMC3674362
Chatterjee, P. et al. Defective chromatin recruitment and retention of NHEJ core components in human tumor cells expressing a Cyclin E fragment. Nucleic Acids Res, 2013; 41: 10157-69.