Diego Rodriguez, a senior biochemistry and psychology double major at Oregon State University, worked to identify and characterize a novel mechanism of the regulation of pro-apoptotic proteins in cancer.
Dysregulation of pro-apoptotic proteins causes an inhibition of apoptotic cell death, leading to increased cell proliferation and resistance to therapy in cancer.
The Broad offers a diverse and collaborative work environment that is focused on solving the world’s biggest biomedical problems. Unsurprisingly, the Broad also excels at creating an atmosphere that fosters the growth and development of scientists. This supportive environment helped catalyze my greater understanding of both biomedical research and of myself as a scientist. The Broad environment has also helped me create connections and build invaluable relationships that will forever impact my life.Therefore, understanding the mechanism by which cancer can dysregulate apoptosis is of clinical importance. WRS17 (William R. Sellers Candidate Protein 17) has been shown to be a modest dependency in specific lineages. By interrogating datasets from several RNAi and CRISPR mediated functional genomics screens, we discovered that loss of WRS17 results in growth defects that are primarily associated with loss of anti-apoptotic genes MCL1, BCL2, BCL-xl, and BCL-w, thus suggesting an anti-apoptotic function for WRS17. WRS17 is predicted to be the substrate recognition component of an Elongin-Cullin-SOCS-box protein (ECS) E3 ubiquitin ligase. Due to the predicted activity, we hypothesized that WRS17 serves as the substrate recognition component of an ECS E3 ubiquitin ligase that specifically targets pro-apoptotic proteins for proteolysis. Using various cellular and biochemical assays, we demonstrated that WRS17 interacts with pro-apoptotic proteins and with other components of the ECS E3 ubiquitin ligases. Further, using the pro-apoptotic protein PUMA we demonstrated WRS17 can catalyze polyubiquitination of pro-apoptotic proteins that leads to degradation by lysosomal autophagy. These studies not only identify and characterize a novel mechanism by which apoptosis is dysregulated in cancer, but further, help create a basis for the investigation of WRS17 as a potential therapeutic target.
Project: WRS17: A Novel Regulator of Pro-Apoptotic Proteins.
Mentor: Debjani Pal, Sellers Lab, Cancer Program