CAREER: Understanding the Non-proteolytic Function of Ubiquitin in Eukaryotic Translesion DNA Synthesis

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Ubiquitin and ubiquitin-like proteins have diverse functions in many fundamentally important cellular processes. Besides the well-known role of ubiquitin in the 26S proteasome-mediated protein degradation pathway, the non-proteolytic roles of ubiquitin are being uncovered at a fast pace. In particular, researchers in the area of DNA damage response have witnessed rapid progress within the past decade. This was largely stimulated by the seminal findings that ubiquitylation and SUMOylation of a key DNA replication/repair protein, proliferating cell nuclear antigen (PCNA), controls precisely how cells respond to different types of DNA damage, and how the different DNA damage repair or tolerance pathways are chosen to cope with the DNA damage. The objective of this CAREER project is twofold: developing chemical approaches for efficient ubiquitylation of PCNA, and using the ubiquitylated PCNA to investigate the molecular mechanism of translesion DNA synthesis in the model organism Saccharomyces cerevisiae. This information will also help researchers in other fields to decipher the non-proteolytic function of ubiquitin in essential cellular processes. Moreover, the newly developed chemical approaches for ubiquitylation can be generalized for investigation of other processes that involve post-translational modification by ubiquitin or ubiquitin-like proteins. Broader ImpactThis CAREER project seeks to spark the scientific curiosity and career aspirations of high school students and underrepresented minorities in chemistry and biology. The interdisciplinary nature of the research and educational activities will equip the undergraduate and graduate students with novel ideas and the most up-to-date experimental skills in the burgeoning field of chemical biology. The outreach activities will also enhance the institutional infrastructure (the virtual reality visualization or CAVE system at the Delaware Biotechnology Institute) that will benefit not only the research community but also the general public. A long-term partnership will be established with the Institute of Genetics, Hungarian Academy of Sciences to facilitate a collaborative effort in attacking this very challenging problem in the DNA damage response. The ultimate goal of this project is to establish research and educational programs that not only advance the field of chemical biology by enhancing the scientific understanding of DNA damage tolerance, but also inspire and educate the next generation of chemical biologists.