2021 Mentored Investigator Grant Recipient — Sridevi Challa, PhD
Sridevi Challa, PhD
UT Southwestern Medical Center
Role of Ribosomal Protein Mono(ADP-ribosyl)ation in Protein Quality Control
Project Summary
Fast dividing cells such as cancer cells require high levels of protein synthesis to support cell growth. But when protein synthesis is too high, the proteins cannot be folded accurately resulting in the accumulation of toxic protein aggregates. Hence cells maintain a balance between protein synthesis and protein clearance, to maintain optimum protein levels. Ribosomes are a hub for this regulation: they are the molecular machines that synthesize proteins, and they also recruit a plethora of proteins to assist in protein clearance. Dysregulation of ribosome function is causative for several disorders such as neurodegeneration and cancer. My preliminary data suggests that a cytosolic Poly(ADPribose) Polymerase (PARP) enzyme maintains this protein homeostasis by regulating the function of ribosomes. I have identified proteins in the ribosome complex that could be regulated by this PARP enzyme and this may play a role in maintaining protein homeostasis. In Aim 1, I will characterize how PARP regulates the group of proteins that could play a role in assembling the ribosome to initiate mRNA translation by identifying the complex assembly using mass spectrometric analysis and its effect on translation by targeted purification of polysomal mRNA-sequencing (TRAP-Seq). In Aim 2, I will examine how perturbations to the PARP-regulated ribosome functions will affect protein synthesis and cell growth in vivo. The completion of this application will result in better understanding of the molecular mechanisms and functions of PARP-regulated protein homeostasis, leading to identification of novel therapeutic agents for ovarian cancers.
This grant is generously supported by The Donald R. and Esther Simon Foundation.
Bio
Dr. Sridevi Challa is an Assistant Professor in the Department of Obstetrics and Gynecology at the University of Chicago. She earned her Ph.D. in Cancer Biology from University of South Florida where she studied the mechanisms of tyrosine kinase signaling in cancers under the mentorship of Dr. Malafa. After being awarded a Ph.D. degree in 2017, she joined the laboratory of Dr. W. Lee Kraus in UT Southwestern Medical Center as a postdoctoral researcher. During her postdoctoral fellowship she identified critical processes regulated by PARP enzymes in ovarian cancers. She demonstrated that the cytosolic NAD+ synthesis pathway controls mono-(ADP-ribosyl)ation of ribosomal proteins which maintains protein homeostasis and supports ovarian cancer cell growth. She was the recipient of an OCRA Mentored Investigator Award.
Dr. Challa joined the Department of Obstetrics and Gynecology at the University of Chicago as an Assistant Professor where she is developing a research program to address critical challenges in the ovarian cancer treatment. Research in her lab focuses on investigating the role of metabolic changes and stress responses in gynecologic cancers. Additionally, with her position as the Basic Science Lead, she is developing the Endometrial Cancer Research Program alongside physicians in the University of Chicago. Support from the OCRA Early Career Investigator Grant will be foundational for achieving her research goals.