60S Ribosomal Subunit Dynamics, mRNA Regulators and TranslationEukaryotic protein synthesis is predominantly regulated at the initiation stage by controlling the function of eukaryotic initiation factors (eIFs) and by regulating the fitness and availability of ribosomes. There are hundreds of accessory 60S maturation factors. Our recent work uncovered a novel signaling mechanism that regulates 60S ribosomal availability and translational rates in response to nutrient stress that is dependent on the accessory factor eIF6. We are currently investigating the structure-function relations of 60S ribosomal maturation factors pre- and post-maturation. We are also focussed on the mechanism of action of mRNA binding oncofetal family of proteins: IMP1 and IMP3. These efforts will help to identify novel targets that will provide parallel or alternate means for cancer therapeutics and for treatment of ribosomopathies such as Shwachman-Diamond-Syndrome.
DNA Repair Mechanisms and
Genomic stability is integral to maintaining cellular fitness and survival. Homologous recombination (HR)-mediated repair of DNA strand breaks is crucial for the maintenance of genomic stability. It is imperative that HR is tightly regulated to ensure that spurious HR or insufficient HR response does not lead to erroneous repair and chromosomal rearrangements. We have recently uncovered novel regulation of HR mediators (RPA, RAD52, BRCA2) specifically in mitosis that plays an important role in maintaining chromosome segregation fidelity. Future studies will aim to understand the cell cycle context-dependent preferential selection of certain repair pathways and its deregulation in disease.
Cancer Signaling Mechanisms
Our research aims to uncover the signaling mechanisms that fuel the rampant growth of cancers and drive the cancer-predisposition of ribosomopathies. Specifically, we are interested in understanding the molecular mechanisms that regulate 60S ribosomal factors and their contributions to translational control and the interplay of DNA repair mechanisms under normal and diseased states including cancer and ribosomopathies. We are also focussed on the mRNA binding oncofetal family of proteins: IMP1 and IMP3 that are exclusively expressed in invasive cancers. We use an array of cellular, molecular, biochemical and in vivo tumor organoid methodologies to address these fundamental mechanistic questions.