Nontranscriptional Function of FOXO1/DAF-16 Contributes to Translesion DNA Synthesis

Abstract

Forkhead box O (FOXO; DAF-16 in nematodes) transcription factors activate a program of genes that control stress resistance, metabolism, and life span. Given the adverse impact of the stochastic DNA damage on organismal development and aging, we examined the role of FOXO/DAF-16 in UV-induced DNA damage response. Knockdown of FOXO1 but not of 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 sustained activation of ATR-Chk1 signaling and a reduction of proliferating cell nuclear antigen (PCNA) monoubiquitination following UV irradiation. FOXO1 does not alter the expression of TLS-related genes, but it binds to replication protein A 1 (RPA1), which 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 a DAF-16 mutant lacking the transactivation domain but not a mutant whose amino acid substitutions render it unable to interact with RPA1. Thus, our findings demonstrate that FOXO1/DAF-16 is a functional component in TLS independent of its transactivation activity.

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Supplemental material for this article may be found at http://dx.doi.org/10.1128/MCB.00265-16.

ACKNOWLEDGMENTS

We thank the Caenorhabditis Genetics Center for the C. elegans strains. We thank the members of the Fukamizu laboratory for their helpful discussions.

This work was supported by Grants-in-Aid for Scientific Research on Priority Areas (number 23116004 to A.F.), Grants-in-Aid for Young Scientists (numbers 20780237 and 22688029 to H.D.), and Grants-in-Aid for JSPS Fellows (number 25.452 to Y.K.) from the Ministry of Education, Culture, Sports, Science, and Technology.

H.D. designed and conducted the experiments, analyzed the data, and wrote and edited the manuscript; Y.K., K.Y. and K.M. designed and conducted the experiments and analyzed the data; S.A., J.-I.S. and Y.T. conducted the experiments and analyzed the data; and A.F. designed the experiments and edited the manuscript.

We declare that we have no conflict of interest.