title: Roles of mutagenic translesion synthesis in mammalian genome stability, health and disease.
abstract: Most spontaneous and DNA damage-induced nucleotide substitutions in eukaryotes depend on translesion synthesis polymerases Rev1 and Pol ζ, the latter consisting of the catalytic subunit Rev3 and the accessory protein Rev7. Here we review the regulation, and the biochemical and cellular functions, of Rev1/Pol ζ-dependent translesion synthesis. These are correlated with phenotypes of mouse models with defects in Rev1, Rev3 or Rev7. The data indicate that Rev1/Pol ζ-mediated translesion synthesis is important for adaptive immunity while playing paradoxical roles in oncogenesis. On the other hand, by enabling the replication of endogenously damaged templates, Rev1/Pol ζ -dependent translesion synthesis protects stem cells, thereby preventing features of ageing. In conclusion, Rev1/Pol ζ-dependent translesion synthesis at DNA helix-distorting nucleotide lesions orchestrates pleiotropic responses that determine organismal fitness and disease.
authors: Department of Human Genetics, Leiden University Medical Center, PO Box 9600, 2300RC Leiden, The Netherlands.
authors: Jacob G
authors: JG
authors: Jansen
authors: Department of Human Genetics, Leiden University Medical Center, PO Box 9600, 2300RC Leiden, The Netherlands.
authors: Anastasia
authors: A
authors: Tsaalbi-Shtylik
authors: Department of Human Genetics, Leiden University Medical Center, PO Box 9600, 2300RC Leiden, The Netherlands. Electronic address: n.de_wind@lumc.nl.
authors: Niels
authors: N
authors: de Wind
mesh_terms: D000818:Animals; D004247:DNA / Q000378:metabolism; D004260:DNA Repair / Q000502:physiology*; D004261:DNA Replication / Q000502:physiology*; D004259:DNA-Directed DNA Polymerase / Q000378:metabolism*; D004194:Disease / Q000235:genetics; D042822:Genomic Instability; D064246:Mad2 Proteins / Q000378:metabolism; D051379:Mice; D016296:Mutagenesis; D009713:Nucleotidyltransferases / Q000378:metabolism; D000099270:Y-Family DNA Polymerases
chemical_list: D004247:DNA; D004259:DNA-Directed DNA Polymerase; D064246:Mad2 Proteins; D009713:Nucleotidyltransferases; C577699:Mad2l2 protein, mouse; C486862:REV3L protein, mouse; C496086:Rev1 protein, mouse; D000099270:Y-Family DNA Polymerases
keywords: DNA damage; DNA translesion synthesis; Genome stability; Mouse models; Replication stress; Rev1; Rev3; Rev7; mutagenesis