Structurally Distinct Complexes of Ubiquitin and Sumo-Modified PCNA Lead to Distinct DNA Damage Response Pathways

Abstract

Ubiquitination of proliferating cell nuclear antigen (PCNA) in response to DNA damage leads to the recruitment of specialized translesion polymerases to the damage locus. This constitutes the initial step in translesion synthesis (TLS) - a critical pathway for cell survival and genome stability. By contrast, PCNA sumoylation leads to suppression of homologous recombination through recruitment of the antirecombinogenic helicase SRS2. How do these similar posttranslational modifications effect such vastly different functional outcomes? We modeled PCNA covalently modified by Ub and SUMO using a multiscale protocol (conjugated docking with the Rosetta package, molecular dynamics and minimal ensemble searches). Our models rationalized the differences in solution scattering data (SAXS) from the PCNA-K164Ub, PCNA-K107Ub and PCNA-K164SUMO complexes. Our results suggest a structural basis for the different functional outcomes of Ub vs. SUMO modification of PCNA.View Large Image | View Hi-Res Image | Download PowerPoint Slide