Replication Fork Slowing and Reversal upon DNA Damage Require PCNA Polyubiquitination and ZRANB3 DNA Translocase Activity

• DOI: 10.1016/j.molcel.2017.08.010
• Publication Date: 2017-09-19T16:03:16Z
• Authors: Marko Vujanovic; Jana Krietsch; Maria Chiara Raso; Nastassja Terraneo; Ralph Zellweger; Jonas A. Schmid; Angelo Taglialatela; Jen-Wei Huang; Cory L. Holland; Katharina Zwicky; Raquel Herrador; Heinz Jacobs; David Cortez; Alberto Ciccia; Lorenza Penengo; Massimo Lopes
• Keywords: Translocase; Fork (system call)

DNA damage tolerance during eukaryotic replication is orchestrated by PCNA ubiquitination. While monoubiquitination activates mutagenic translesion synthesis, polyubiquitination an error-free pathway, elusive in mammals, enabling bypass template switching. Fork reversal driven vitro multiple enzymes, including the translocase ZRANB3, shown to bind polyubiquitinated PCNA. However, whether this interaction promotes fork remodeling and switching vivo was unknown. Here we show that damage-induced mammalian cells requires ubiquitination, UBC13, K63-linked polyubiquitin chains, previously involved tolerance. also ZRANB3 activity its with PCNA, pinpointing as a key effector of Mutations affecting induced unrestrained progression chromosomal breakage, suggesting global slowing protection mechanism. Targeting these systems represents promising strategy potentiate cancer chemotherapy.