Regulation of Genome Maintenance by Chromatin-Associated Protein Degradation

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Accumulation of DNA lesions causes the induction of the cellular DNA damage response to maintain genome stability. DNA double-strand breaks (DSBs) result from defects in DNA replication or genotoxic insults such as ionizing radiation, radiomimetic chemicals, or reactive oxygen species. Interestingly, the subsequent induction of the DDR is tightly regulated by ubiquitin modification. Our recent work revealed a central role of the ubiquitin-selective chaperone CDC-48/p97 in DNA replication and DSB repair, regulating the activity and turnover of ubiquitylated proteins bound to chromatin. However, in contrast to its well-established function in protein quality control, the mechanistic role of CDC-48/p97 in chromatin-associated protein degradation and genome maintenance is unclear. The central objective of our proposed research is to define the molecular role of CDC-48/p97 in chromatin-associated processes important for DNA metabolism and genome surveillance. Given its key activity as a ubiquitin-selective segregase, understanding how CDC-48/p97 regulates cell cycle progression and DNA repair would provide novel insights into the cross talk between ubiquitin, genome stability, and cancer development.