Stalled Polη at its cognate substrate initiates an alternative translesion synthesis pathway via interaction with REV1

摘要

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 Poln interactswith REV1, and REV1 interacts with other TLS polymerases including Poli, Polκ and Poll, Poln 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 Poln activity but also by dysfunction of network between Poln and other TLS polymerases. Here, we examined whether the TLS polymerase network via Poln is important for replicative bypass of CPDs and DNA damage tolerance induced by UV in mouse cells. Weobserved that UV sensitivity of Poln-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 Poln and REV1. However, expression of the inactive mutant Poln 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 Poln–REV1 interaction when Polη fails to bypass its cognate substrates.