60S Subunit Dynamics and Translation
Eukaryotic 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. Our recent work has uncovered a novel signaling mechanism that regulates ribosomal availability and translational rates in response to nutrient stress. We are currently investigating the structure-function relationships of 60S ribosomal maturation factors, Ribosome Quality Control (RQC), and the 60S ribosomal structural dynamics that are critical for stress response. 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
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 regulate critical cellular processes based on the polarizing physiological cues of growth and stress. We are primarily interested in understanding the molecular mechanisms that regulate the 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 use an array of cellular, molecular, biochemical and in vivo tumor organoid methodologies to address these fundamental mechanistic questions.