The BRCT domain of mammalian Rev1 is involved in regulating DNA translesion synthesis.
Rev1 is a deoxycytidyl transferase associated with DNA translesion synthesis (TLS). In addition to its catalytic domain, Rev1 possesses a so-called BRCA1 C-terminal (BRCT) domain. Here, we describe cells and mice containing a targeted deletion of this domain. Rev1(B/B) mice are healthy, fertile and display normal somatic hypermutation. Rev1(B/B) cells display an elevated spontaneous frequency of intragenic deletions at Hprt. In addition, these cells were sensitized to exogenous DNA damages. Ultraviolet-C (UV-C) light induced a delayed progression through late S and G2 phases of the cell cycle and many chromatid aberrations, specifically in a subset of mutant cells, but not enhanced sister chromatid exchanges (SCE). UV-C-induced mutagenesis was reduced and mutations at thymidine-thymidine dimers were absent in Rev1(B/B) cells, the opposite phenotype of UV-C-exposed cells from XP-V patients, lacking TLS polymerase eta. This suggests that the enhanced UV-induced mutagenesis in XP-V patients may depend on error-prone Rev1-dependent TLS. Together, these data indicate a regulatory role of the Rev1 BRCT domain in TLS of a limited spectrum of endogenous and exogenous nucleotide damages during a defined phase of the cell cycle.
Jansen
Jacob G
JG
Department of Toxicogenetics, Leiden University Medical Center 2300 RA Leiden, The Netherlands.
Tsaalbi-Shtylik
Anastasia
A
Langerak
Petra
P
Calléja
Fabienne
F
Meijers
Caro M
CM
Jacobs
Heinz
H
de Wind
Niels
N
D000818:Animals; D019313:BRCA1 Protein / Q000737:chemistry; D002453:Cell Cycle / Q000528:radiation effects; D002869:Chromosome Aberrations; D004247:DNA / Q000096:biosynthesis; D004249:DNA Damage; D004261:DNA Replication; D004259:DNA-Directed DNA Polymerase; D004622:Embryo, Mammalian / Q000166:cytology; D051379:Mice; D016296:Mutagenesis; D009713:Nucleotidyltransferases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary; D012854:Sister Chromatid Exchange; D013234:Stem Cells / Q000166:cytology / Q000528:radiation effects / Q000648:ultrastructure; D014466:Ultraviolet Rays; D000099270:Y-Family DNA Polymerases
D019313:BRCA1 Protein; D004247:DNA; D004259:DNA-Directed DNA Polymerase; D009713:Nucleotidyltransferases; C496086:Rev1 protein, mouse; D000099270:Y-Family DNA Polymerases