Niladri Sinha

Our laboratory is focused on studying key aspects of protein synthesis and translational control in healthy and diseased states. We broadly investigate (1) the role of ribosomes as critical sensors of cellular stress and (2) focus on identifying and characterizing ribosome-mediated quality control and signaling pathways that regulate cellular homeostasis and cell fate decisions during translational stress. The dysregulation of these critical surveillance pathways leads to ribosome impairment and breakdown of proteostasis, and has been associated with cancer, aging, and various metabolic and neurodegenerative disorders.

Our research broadly aims to uncover mechanisms that enable cells to identify and resolve disruptions during protein synthesis. We focus on ribosomal collisions, which occur when stalled ribosomes are rear-ended on damaged mRNAs during faulty elongation. While collisions have been recognized as crucial for detecting aberrant translation, the key regulators of various ribosome-mediated quality control (QC) and signaling pathways remain poorly characterized. We use a combination of biochemical, proteomic, and genetic approaches to identify and characterize regulators of ribosome-mediated stress responses. In previous work, we discovered a QC factor called EDF1 that acts as an “early responder” during ribosomal collisions and plays a central role in restoring translational homeostasis (Sinha et al., eLife 2020). More recently, we discovered that the ribotoxic stress response, rather than the DNA damage response, plays a dominant role in determining cell fate outcomes following UV exposure (Sinha et al., Cell 2024). This pathway, regulated by the protein kinase ZAK, is activated in response to ribosomal collisions and determines whether a cell will survive or undergo apoptosis based on the extent of ribosomal and RNA damage. Our findings established ribosomes as physiological sensors of UV-induced cellular damage, playing pivotal roles in determining cellular fate (Sinha et al., Cell 2024).

Prospective graduate students will build on these findings to characterize fundamental mechanisms of ribosome-mediated stress responses regulated by QC factors and protein kinases following disruptions to protein homeostasis using various biochemical, proteomic, cryo-EM, and genetic approaches. Our long-term goal is to harness these mechanisms to target inherent vulnerabilities in cells that display unusually high protein synthesis rates, such as cancer cells, as well as in aging cells with abnormalities in proteostasis and protein turnover.

We are committed to fostering a dynamic, collaborative, and scientifically rigorous environment. We welcome curiosity-driven individuals excited to make foundational discoveries aimed at understanding and combating defects in proteostasis and translational control.

Key projects

1. Mechanisms that enable cells restore proteostasis following translational stress.
2. Mechanisms regulating the Ribotoxic Stress Response during translational stress.
3. Mechanisms regulating translational repression through the Integrated Stress Response pathway during ribotoxic stress.