title: Non-transcriptional Function of FOXO1/DAF-16 Contributes to Translesion DNA Synthesis.
abstract: Forkhead box O (FOXO; DAF-16 in nematode) transcription factors activate a program of genes that control stress resistance, metabolism, and lifespan. Given the adverse impact of the stochastic DNA damage on organismal development and ageing, we examined the role of FOXO/DAF-16 in UV-induced DNA-damage response. Knockdown of FOXO1, but not FOXO3a, increases sensitivity to UV irradiation when exposed during S phase, suggesting a contribution of FOXO1 to translesion DNA synthesis (TLS), a replicative bypass of UV-induced DNA lesions. Actually, FOXO1 depletion results in a sustained activation of the ATR-Chk1 signaling and a reduction of PCNA monoubiquitination following UV irradiation. FOXO1 does not alter the expression of TLS-related genes but binds to the protein replication protein A (RPA1) that coats single-stranded DNA and acts as a scaffold for TLS. In Caenorhabditis elegans, daf-16 null mutants show UV-induced retardation in larval development and are rescued by overexpressing DAF-16 mutant lacking transactivation domain, but not substitution mutant unable to interact with RPA-1. Thus, our findings demonstrate that FOXO1/DAF-16 is a functional component in TLS independently of its transactivation activity.
authors.affiliation: Life Science Center, Tsukuba Advanced Research Alliance Graduate School of Life and Environmental Sciences , University of Tsukuba, 1-1-1 Tennoudai, Tsukuba, Ibaraki, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Daitoku
authors.affiliation: Graduate School of Life and Environmental Sciences , University of Tsukuba, 1-1-1 Tennoudai, Tsukuba, Ibaraki, Japan.
authors.forename: Yuta
authors.initials: Y
authors.lastname: Kaneko
authors.affiliation: Graduate School of Life and Environmental Sciences , University of Tsukuba, 1-1-1 Tennoudai, Tsukuba, Ibaraki, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Yoshimochi
authors.affiliation: Graduate School of Life and Environmental Sciences , University of Tsukuba, 1-1-1 Tennoudai, Tsukuba, Ibaraki, Japan.
authors.forename: Kaori
authors.initials: K
authors.lastname: Matsumoto
authors.affiliation: Graduate School of Life and Environmental Sciences , University of Tsukuba, 1-1-1 Tennoudai, Tsukuba, Ibaraki, Japan.
authors.forename: Sho
authors.initials: S
authors.lastname: Araoi
authors.affiliation: Graduate School of Life and Environmental Sciences , University of Tsukuba, 1-1-1 Tennoudai, Tsukuba, Ibaraki, Japan.
authors.forename: Jun-Ichi
authors.initials: JI
authors.lastname: Sakamaki
authors.affiliation: Life Science Center, Tsukuba Advanced Research Alliance.
authors.forename: Yuta
authors.initials: Y
authors.lastname: Takahashi
authors.affiliation: Life Science Center, Tsukuba Advanced Research Alliance Graduate School of Life and Environmental Sciences , University of Tsukuba, 1-1-1 Tennoudai, Tsukuba, Ibaraki, Japan akif@tara.tsukuba.ac.jp.
authors.forename: Akiyoshi
authors.initials: A
authors.lastname: Fukamizu