title: Separate domains of Rev1 mediate two modes of DNA damage bypass in mammalian cells.
abstract: The Y family DNA polymerase Rev1 has been proposed to play a regulatory role in the replication of damaged templates. To elucidate the mechanism by which Rev1 promotes DNA damage bypass, we have analyzed the progression of replication on UV light-damaged DNA in mouse embryonic fibroblasts that contain a defined deletion in the N-terminal BRCT domain of Rev1 or that are deficient for Rev1. We provide evidence that Rev1 plays a coordinating role in two modes of DNA damage bypass, i.e., an early and a late pathway. The cells carrying the deletion in the BRCT domain are deficient for the early pathway, reflecting a role of the BRCT domain of Rev1 in mutagenic translesion synthesis. Rev1-deficient cells display a defect in both modes of DNA damage bypass. Despite the persistent defect in the late replicational bypass of fork-blocking (6-4)pyrimidine-pyrimidone photoproducts, overall replication is not strongly affected by Rev1 deficiency. This results in almost completely replicated templates that contain gaps encompassing the photoproducts. These gaps are inducers of DNA damage signaling leading to an irreversible G(2) arrest. Our results corroborate a model in which Rev1-mediated DNA damage bypass at postreplicative gaps quenches irreversible DNA damage responses.
authors.affiliation: Department of Toxicogenetics, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Jacob G
authors.initials: JG
authors.lastname: Jansen
authors.forename: Anastasia
authors.initials: A
authors.lastname: Tsaalbi-Shtylik
authors.forename: Giel
authors.initials: G
authors.lastname: Hendriks
authors.forename: Himabindu
authors.initials: H
authors.lastname: Gali
authors.forename: Ayal
authors.initials: A
authors.lastname: Hendel
authors.forename: Fredrik
authors.initials: F
authors.lastname: Johansson
authors.forename: Klaus
authors.initials: K
authors.lastname: Erixon
authors.forename: Zvi
authors.initials: Z
authors.lastname: Livneh
authors.forename: Leon H F
authors.initials: LH
authors.lastname: Mullenders
authors.forename: Lajos
authors.initials: L
authors.lastname: Haracska
authors.forename: Niels
authors.initials: N
authors.lastname: de Wind