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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.

SUBMITTER: Daitoku H 

PROVIDER: S-EPMC5064221 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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Non-transcriptional Function of FOXO1/DAF-16 Contributes to Translesion DNA Synthesis.

Daitoku Hiroaki H   Kaneko Yuta Y   Yoshimochi Kenji K   Matsumoto Kaori K   Araoi Sho S   Sakamaki Jun-Ichi JI   Takahashi Yuta Y   Fukamizu Akiyoshi A  

Molecular and cellular biology 20160822 21


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 replicati  ...[more]

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