title: Stalled Polη at its cognate substrate initiates an alternative translesion synthesis pathway via interaction with REV1.
abstract: DNA polymerase η (Polη), whose gene mutation is responsible for the inherited disorder xeroderma pigmentosum variant (XP-V), carries out accurate and efficient translesion synthesis (TLS) across cyclobutane pyrimidine dimer (CPD). As Polη interacts with REV1, and REV1 interacts with other TLS polymerases including Polι, Polκ and Polζ, Polη may play a role in recruitment of these TLS polymerases at lesion site. But it is unclear whether UV sensitivity of XP-V patients is caused not only by defect of Polη activity but also by dysfunction of network between Polη and other TLS polymerases. Here, we examined whether the TLS polymerase network via Polη is important for replicative bypass of CPDs and DNA damage tolerance induced by UV in mouse cells. We observed that UV sensitivity of Polη-deficient mouse cells was moderately rescued by the expression of a catalytically inactive Polη. Moreover, this recovery of cellular UV sensitivity was mediated by the interaction between Polη and REV1. However, expression of the inactive mutant Polη was not able to suppress the incidence of UV-induced mutation observed in Polη-deficient cells. We propose the model that REV1 and Polκ are involved in DNA damage tolerance via Polη-REV1 interaction when Polη fails to bypass its cognate substrates.
authors.affiliation: Faculty of Science, Gakushuin University, 1-5-1 Mejiro, Toshima-Ku, Tokyo 171-8588, Japan.
authors.forename: Wakana
authors.initials: W
authors.lastname: Ito
authors.forename: Masayuki
authors.initials: M
authors.lastname: Yokoi
authors.forename: Nobutaka
authors.initials: N
authors.lastname: Sakayoshi
authors.forename: Yasutaka
authors.initials: Y
authors.lastname: Sakurai
authors.forename: Jun-Ichi
authors.initials: J
authors.lastname: Akagi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Mitani
authors.forename: Fumio
authors.initials: F
authors.lastname: Hanaoka
mesh_terms: D000818:Animals; D002460:Cell Line; D004261:DNA Replication / Q000502:physiology; D004259:DNA-Directed DNA Polymerase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation / Q000528:radiation effects; D051379:Mice; D009713:Nucleotidyltransferases / Q000378:metabolism*; D011485:Protein Binding; D013379:Substrate Specificity; D014466:Ultraviolet Rays; D014983:Xeroderma Pigmentosum / Q000235:genetics / Q000378:metabolism; D000099270:Y-Family DNA Polymerases
chemical_list: D004259:DNA-Directed DNA Polymerase; D009713:Nucleotidyltransferases; C498613:Polk protein, mouse; D000099270:Y-Family DNA Polymerases; C112338:Rad30 protein; C496086:Rev1 protein, mouse