Research Interests
Our research aims to explore the role and regulation of protein synthesis based on the physiological context. Regulation of gene expression at the translational level provides a temporal advantage by eliciting rapid fluctuations in protein levels in response to changes in the cellular environment. In response to diverse physiological and pathological states, several signaling pathways are activated that converge on the translational machinery to alter the rates and types of protein being synthesized. The pervasiveness of translational control is evident in the genesis and progression of diseases such as cancer, neruodegeneration, and infections that are often a consequence of deregulated protein synthesis. Such deregulation presents an excellent opportunity to selectively target the translational machinery for therapeutic advancement.
Eukaryotic translation initiation factor 6 (eIF6) and 60S ribosomal subunit
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Eukaryotic protein synthesis is predominantly regulated at the initiation stage by controlling the function of eukaryotic initiation factors and by regulating the fitness and availability of ribosomes. Based on the cellular context, upstream signaling pathways regulate eIFs by altering their levels, or their activities via post-translational modifications such as methylation, phosphorylation or by reorganizing their spatial distribution. eIF6 is a key regulator of 60S biogenesis and activity. Our recent work has identified novel post-translational modification of eIF6 that is dependent on the state of growth or stress. We are currently exploring the effect of these post-translational modifications in altering eIF6 and 60S dynamics.
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Simplified Schematic of eIF6 function in 60S synthesis, maturation and association with 40S
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Translational and Ribosomal Control of Cancer
Since the 1800s, enlarged nucleoli are considered a hallmark of cancer cells. Enlarged nucleoli serve as hubs of enhanced ribosome biogenesis, thereby leading to increased production of proteins that sustain the uncontrolled growth and proliferation of cancer cells. Our research is focused on understanding the contributions of translational control towards tumor initiation and progression towards malignancy. We are currently investigating the interplay of oncogenes and tumor suppressors in regulating eIFs and other translational factors. These efforts will help to identify novel targets that will eventually provide parallel or alternate means for cancer therapeutics.
Protein Synthesis and Stem cells
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Adult stem cells are essential for maintaining tissue integrity by serving as a renewed source of cells. Interestingly, most adult stem cells exhibit lower rates of protein synthesis compared to their progenitor cells. It is unclear as to how such low rates of protein synthesis are maintained in stem cells and how they influence the stem cell response to stress. Protein synthesis regulation in adult stem cells in vastly under explored. We are interested in understanding the mechanisms that regulate the translation initiation machinery and influence the protein synthesis rates in adult stem cells. Our efforts are aimed at understanding the fundamental biology of adult stem cells, which will help to expand the application of stem cells in regenerative medicine, and for treatment of cancer and other diseases.
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Murine stem cell enriched spheroids
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Collaborative Project: DNA Repair: Modulators of Homologous Recombination
HR-mediated repair of DNA double strand breaks is crucial for the maintenance of genomic stability. However, it is imperative that HR is tightly regulated to ensure that spurious HR does not lead to additional genomic changes and lead to chromosomal rearrangements. We are working closely with our collaborators to understand the modulators of the initial stages of HR such as RPA, Rad51 and their effects on cellular checkpoint responses by Chk1 and p53-pathways.
HR-mediated repair of DNA double strand breaks is crucial for the maintenance of genomic stability. However, it is imperative that HR is tightly regulated to ensure that spurious HR does not lead to additional genomic changes and lead to chromosomal rearrangements. We are working closely with our collaborators to understand the modulators of the initial stages of HR such as RPA, Rad51 and their effects on cellular checkpoint responses by Chk1 and p53-pathways.
