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DNA damage tolerance during eukaryotic replication is orchestrated by PCNA ubiquitination. While monoubiquitination activates mutagenic translesion synthesis, polyubiquitination activates an error-free pathway, elusive in mammals, enabling damage bypass by template switching. Fork reversal is driven in vitro by multiple enzymes, including the DNA translocase ZRANB3, shown to bind polyubiquitinated PCNA. However, whether this interaction promotes fork remodeling and template switching in vivo was unknown. Here we show that damage-induced fork reversal in mammalian cells requires PCNA ubiquitination, UBC13, and K63-linked polyubiquitin chains, previously involved in error-free damage tolerance. Fork reversal in vivo also requires ZRANB3 translocase activity and its interaction with polyubiquitinated PCNA, pinpointing ZRANB3 as a key effector of error-free DNA damage tolerance. Mutations affecting fork reversal also induced unrestrained fork progression and chromosomal breakage, suggesting fork remodeling as a global fork slowing and protection mechanism. Targeting these fork protection systems represents a promising strategy to potentiate cancer chemotherapy.
Pubmed ID: 28886337 RIS Download
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Commercial vendor and service provider of laboratory reagents and antibodies. Supplier of scientific instrumentation, reagents and consumables, and software services.
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View all literature mentionsA commercial graphing software company that offers scientific software for statistical analyses, curve fitting and data analysis. It offers four programs: Prism, InStat, StatMate and QuickCalcs.
View all literature mentionsSoftware for single-cell flow cytometry analysis. Its functions include management, display, manipulation, analysis and publication of the data stream produced by flow and mass cytometers.
View all literature mentionsProteintech Europe Ltd is an ISO 9001:2008 certified company
View all literature mentionsCell line HCT 116 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsCell line HEK293T is a Transformed cell line with a species of origin Homo sapiens (Human)
View all literature mentionsCell line U2OS is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsThis monoclonal targets Ubiquitin
View all literature mentionsThis polyclonal targets Lamin A (C-terminal) antibody produced in rabbit
View all literature mentionsThis unknown targets Rat IgG (H+L)
View all literature mentionsThis polyclonal secondary targets IgG (H+L)
View all literature mentionsThis monoclonal targets BrdU
View all literature mentionsThis polyclonal targets TFIIH p89 (S-19)
View all literature mentionsThis polyclonal targets Blooms Syndrome Protein Blm
View all literature mentionsThis monoclonal targets Glyceraldehyde-3-PDH (GAPDH)
View all literature mentionsThis monoclonal targets PCNA (PC10)
View all literature mentionsThis polyclonal targets beta Tubulin (H-235)
View all literature mentionsThis monoclonal targets UBC13
View all literature mentionsThis polyclonal secondary targets IgG (H+L)
View all literature mentionsThis monoclonal targets Ubiquitin
View all literature mentionsThis polyclonal targets Lamin A (C-terminal) antibody produced in rabbit
View all literature mentionsThis unknown targets Rat IgG (H+L)
View all literature mentionsThis monoclonal targets BrdU
View all literature mentionsThis polyclonal targets TFIIH p89 (S-19)
View all literature mentionsThis polyclonal targets Blooms Syndrome Protein Blm
View all literature mentionsThis monoclonal targets Glyceraldehyde-3-PDH (GAPDH)
View all literature mentionsThis monoclonal targets PCNA (PC10)
View all literature mentionsThis polyclonal targets beta Tubulin (H-235)
View all literature mentionsThis monoclonal targets UBC13
View all literature mentionsThis polyclonal targets beta Tubulin (H-235)
View all literature mentionsThis monoclonal targets UBC13
View all literature mentionsThis polyclonal targets Lamin A (C-terminal) antibody produced in rabbit
View all literature mentionsThis unknown targets Rat IgG (H+L)
View all literature mentionsThis monoclonal targets Ubiquitin
View all literature mentionsThis polyclonal secondary targets IgG (H+L)
View all literature mentionsThis monoclonal targets BrdU
View all literature mentionsThis polyclonal targets Blooms Syndrome Protein Blm
View all literature mentionsThis polyclonal targets TFIIH p89 (S-19)
View all literature mentionsThis monoclonal targets Glyceraldehyde-3-PDH (GAPDH)
View all literature mentionsThis monoclonal targets PCNA (PC10)
View all literature mentionsThis monoclonal targets UBC13
View all literature mentionsThis polyclonal targets beta Tubulin (H-235)
View all literature mentionsThis monoclonal targets PCNA (PC10)
View all literature mentionsThis monoclonal targets BrdU
View all literature mentionsThis monoclonal targets Glyceraldehyde-3-PDH (GAPDH)
View all literature mentionsThis polyclonal targets Blooms Syndrome Protein Blm
View all literature mentionsThis polyclonal targets TFIIH p89 (S-19)
View all literature mentionsThis polyclonal targets Lamin A (C-terminal) antibody produced in rabbit
View all literature mentionsThis monoclonal targets Ubiquitin
View all literature mentionsThis polyclonal secondary targets IgG (H+L)
View all literature mentionsThis unknown targets Rat IgG (H+L)
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