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- W2526619989 abstract "Flap endonuclease 1 (FEN1) phosphorylation is proposed to regulate the action of FEN1 inDNArepair as well as Okazaki fragment maturation. However, the biologic significance of FEN1 phosphorylation in response to DNA damage remains unknown. Here, we report an in vivo role for FEN1 phosphorylation, using a mouse line carrying S187A FEN1, which abolishes FEN1 phosphorylation. Although S187A mouse embryonic fibroblast cells showed normal proliferation under low oxygen levels (2%), the mutant cells accumulated oxidative DNA damage, activated DNA damage checkpoints, and showed G1-phase arrest at atmospheric oxygen levels (21%). This suggests an essential role for FEN1 phosphorylation in repairing oxygen-induced DNA damage and maintaining proper cell cycle progression. Consistently, the mutant cardiomyocytes showed G1-phase arrest due to activation of the p53-mediated DNA damage response at the neonatal stage, which reduces the proliferation potential of the cardiomyocytes and impairs heart development. Nearly 50%of new borns with the S187 A mutant died in the first week due to failure to undergo the peroxisome proliferator-activated receptor signaling-dependent switch from glycolysis to fatty acid oxidation. The adult mutant mice developed dilated hearts and showed significantly shorter life spans. Altogether, our results reveal an important role of FEN1 phosphorylation to counteract oxygen-induced stress in the heart during the fetal-to-neonatal transition.—Zhou, L., Dai, H., Wu, J., Zhou, M., Yuan, H., Du, J., Yang, L., Wu, X., Xu, H., Hua, Y., Xu, J., Zheng, L., Shen, B. Role of FEN1 S187 phosphorylation in counteracting oxygen-induced stress and regulating postnatal heart development. FASEB J. 31, 132–147 (2017) www.fasebj.org" @default.
- W2526619989 created "2016-10-07" @default.
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- W2526619989 date "2016-09-30" @default.
- W2526619989 modified "2023-10-14" @default.
- W2526619989 title "Role of FEN1 S187 phosphorylation in counteracting oxygen‐induced stress and regulating postnatal heart development" @default.
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- W2526619989 doi "https://doi.org/10.1096/fj.201600631r" @default.
- W2526619989 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/5161519" @default.
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