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A Degenerate PCNA-Interacting Peptide (DPIP) box targets RNF168 to replicating DNA to limit 53BP1 signaling

By Yang Yang, Deepika Jayaprakash, Robert Hollingworth, Steven Chen, Amy Jablonski, Elizebath Mutter-Rottmayer, Yanzhe Gao, Jay Anand Ramlal, Jing An, Xing Chen, Kenneth Pearce, Sophie-Anne Blanchet, Amelie Fradet-Turcotte, Grant Stewart, Cyrus Vaziri

Posted 18 Mar 2021
bioRxiv DOI: 10.1101/2021.03.17.435897

The E3 ligase RNF168 has been suggested to have roles at DNA replication forks in addition to its canonical functions in DNA double-strand break (DSB) signaling. However, the precise role of RNF168 in DNA replication remains unclear. Here we demonstrate that RNF168 is recruited to DNA replication factories independent of the canonical DSB response pathway regulators and identify a degenerate PCNA-Interacting Peptide (DPIP) motif in the C-terminus of RNF168 which mediates its binding to PCNA. An RNF168 mutant harboring substitutions in the DPIP box fails to interact with PCNA and is not recruited to sites of DNA synthesis, yet fully retains its ability to promote DSB-induced 53BP1 foci. Surprisingly, the RNF168 DPIP mutant also retains the ability to support ongoing DNA replication fork movement, demonstrating that PCNA-binding is dispensable for normal S-phase functions. However, replisome-associated RNF168 functions to suppress the DSB-induced 53BP1 DNA damage response during S-phase. Moreover, we show that WT RNF168 can perform PCNA ubiquitylation independently of RAD18 and also synergizes with RAD18 to amplify PCNA ubiquitylation. Taken together, our results identify non-canonical functions of RNF168 at the replication fork and demonstrate new mechanisms of cross talk between the DNA damage and replication stress response pathways.

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