PCNA-binding activity separates RNF168 functions in DNA replication and DNA double-stranded break signaling.

Publisher: Oxford University Press Country of Publication: England NLM ID: 0411011 Publication Model: Print Cited Medium: Internet ISSN: 1362-4962 (Electronic) Linking ISSN: 03051048 NLM ISO Abbreviation: Nucleic Acids Res Subsets: MEDLINE

Publication: 1992- : Oxford : Oxford University Press
Original Publication: London, Information Retrieval ltd.

Proliferating Cell Nuclear Antigen*/metabolism ; Proliferating Cell Nuclear Antigen*/genetics ; Ubiquitin-Protein Ligases*/metabolism ; Ubiquitin-Protein Ligases*/genetics ; DNA Breaks, Double-Stranded* ; DNA Replication* ; Signal Transduction* ; DNA-Binding Proteins*/metabolism ; DNA-Binding Proteins*/genetics ; Protein Binding*; Humans ; Tumor Suppressor p53-Binding Protein 1/metabolism ; Tumor Suppressor p53-Binding Protein 1/genetics ; Ataxia Telangiectasia Mutated Proteins/metabolism ; Ataxia Telangiectasia Mutated Proteins/genetics ; DNA Repair ; Ubiquitination ; HEK293 Cells

RNF168 orchestrates a ubiquitin-dependent DNA damage response to regulate the recruitment of repair factors, such as 53BP1 to DNA double-strand breaks (DSBs). In addition to its canonical functions in DSB signaling, RNF168 may facilitate DNA replication fork progression. However, the precise role of RNF168 in DNA replication remains unclear. Here, we demonstrate that RNF168 is recruited to DNA replication factories in a manner that is independent of the canonical DSB response pathway regulated by Ataxia-Telangiectasia Mutated (ATM) and RNF8. We identify a degenerate Proliferating Cell Nuclear Antigen (PCNA)-interacting peptide (DPIP) motif in the C-terminus of RNF168, which together with its Motif Interacting with Ubiquitin (MIU) domain mediates binding to mono-ubiquitylated PCNA at replication factories. An RNF168 mutant harboring inactivating substitutions in its DPIP box and MIU1 domain (termed RNF168 ΔDPIP/ΔMIU1) is not recruited to sites of DNA synthesis and fails to support ongoing DNA replication. Notably, the PCNA interaction-deficient RNF168 ΔDPIP/ΔMIU1 mutant fully rescues the ability of RNF168-/- cells to form 53BP1 foci in response to DNA DSBs. Therefore, RNF168 functions in DNA replication and DSB signaling are fully separable. Our results define a new mechanism by which RNF168 promotes DNA replication independently of its canonical functions in DSB signaling.
(© The Author(s) 2024. Published by Oxford University Press on behalf of Nucleic Acids Research.)

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University of Birmingham; P30 CA016086 United States CA NCI NIH HHS; UNC Lineberger Comprehensive Cancer Center; S10OD030223 United States NH NIH HHS; 152948 Canada CAPMC CIHR; C17183/A23303 Cancer Research-UK Programme; R01 CA279034 United States CA NCI NIH HHS

0 (Proliferating Cell Nuclear Antigen)
EC 2.3.2.27 (Ubiquitin-Protein Ligases)
EC 2.3.2.27 (RNF168 protein, human)
0 (DNA-Binding Proteins)
0 (Tumor Suppressor p53-Binding Protein 1)
EC 2.7.11.1 (Ataxia Telangiectasia Mutated Proteins)
0 (TP53BP1 protein, human)
0 (PCNA protein, human)
0 (RNF8 protein, human)

Date Created: 20241024 Date Completed: 20241127 Latest Revision: 20241130

20241202

PMC11602139

10.1093/nar/gkae918

39445802