Understanding how cells orchestrate the response to DNA damage during S-phase is critical. DNA damage can stall the replication machinery and delay the cellular replication program. The restart of stalled replication forks is mediated by the replication protein PCNA, a ring-shaped molecule that encircles DNA and acts as a processivity factor for DNA polymerases. Post-translational modification of PCNA with ubiquitin at stalled replication forks has been proposed to promote Translesion Synthesis-mediated lesion bypass. In order to understand these events at the molecular level, we generated PCNA ubiquitination-deficient cell lines using CRISPR/Cas9 technology. Our studies identified an essential role of PCNA ubiquitination for DNA replication and replication-associated mutagenesis. Moreover, we identified the ubiquitin ligase HUWE1 as a novel mediator of PCNA-dependent fork restart.

Central role of PCNA in promoting replication of damaged DNA

254th National Meeting (2017)

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