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

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...

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Veröffentlicht in:Molecular cell Jg. 67; H. 5; S. 882
Hauptverfasser: Vujanovic, Marko, Krietsch, Jana, Raso, Maria Chiara, Terraneo, Nastassja, Zellweger, Ralph, Schmid, Jonas A, Taglialatela, Angelo, Huang, Jen-Wei, Holland, Cory L, Zwicky, Katharina, Herrador, Raquel, Jacobs, Heinz, Cortez, David, Ciccia, Alberto, Penengo, Lorenza, Lopes, Massimo
Format: Journal Article
Sprache:Englisch
Veröffentlicht: United States 07.09.2017
Schlagworte:
Animals
CRISPR-Cas Systems
DNA Damage
DNA Helicases - genetics
DNA Helicases - metabolism
DNA Replication
DNA, Neoplasm - biosynthesis
DNA, Neoplasm - genetics
DNA, Neoplasm - ultrastructure
HCT116 Cells
HEK293 Cells
Humans
Kinetics
Mice
Mutation
Neoplasms - enzymology
Neoplasms - genetics
Neoplasms - ultrastructure
Polyubiquitin - metabolism
Proliferating Cell Nuclear Antigen - genetics
Proliferating Cell Nuclear Antigen - metabolism
Replication Origin
RNA Interference
Transfection
Ubiquitin-Conjugating Enzymes - genetics
Ubiquitin-Conjugating Enzymes - metabolism
Ubiquitination
DNA damage tolerance
cancer chemotherapeutics
ZRANB3 DNA translocase
PCNA ubiquitination
single-molecule approaches
electron microscopy in vivo
postreplication repair
replication fork reversal
replication fork progression
ISSN:1097-4164, 1097-4164
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Zusammenfassung: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.
Bibliographie:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
ISSN:1097-4164
1097-4164
DOI:10.1016/j.molcel.2017.08.010