Role of FEN1 S187 phosphorylation in counteracting oxygen-induced stress and regulating postnatal heart development.
Flap endonuclease 1 (FEN1) phosphorylation is proposed to regulate the action of FEN1 in DNA repair 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 newborns with the S187A 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.
College of Life Sciences and Institute of Nuclear-Agricultural Sciences, Zhejiang University, Hangzhou, China.|Department of Cancer Genetics and Epigenetics and Beckman Research Institute of City of Hope, Duarte, California, USA.
Lina
L
Zhou
Department of Cancer Genetics and Epigenetics and Beckman Research Institute of City of Hope, Duarte, California, USA.
Huifang
H
Dai
Center for Craniofacial Molecular Biology, Herman Ostrow School of Dentistry, University of Southern California, Los Angeles, California, USA.
Jian
J
Wu
Department of Cancer Genetics and Epigenetics and Beckman Research Institute of City of Hope, Duarte, California, USA.
Mian
M
Zhou
Department of Diagnostic Ultrasound, Shaoxing Women and Children's Hospital, Shaoxing, China.
Hua
H
Yuan
Department of Cancer Genetics and Epigenetics and Beckman Research Institute of City of Hope, Duarte, California, USA.
Juan
J
Du
Department of Molecular and Cellular Biology, Beckman Research Institute of City of Hope, Duarte, California, USA; and.
Lu
L
Yang
Department of Molecular and Cellular Biology, Beckman Research Institute of City of Hope, Duarte, California, USA; and.
Xiwei
X
Wu
Key Laboratory of Chinese Ministry of Agriculture for Nuclear-Agricultural Sciences, Institute of Nuclear-Agricultural Sciences, Zhejiang University, Hangzhou, China.
Hong
H
Xu
Key Laboratory of Chinese Ministry of Agriculture for Nuclear-Agricultural Sciences, Institute of Nuclear-Agricultural Sciences, Zhejiang University, Hangzhou, China.
Yuejin
Y
Hua
Center for Craniofacial Molecular Biology, Herman Ostrow School of Dentistry, University of Southern California, Los Angeles, California, USA.
Jian
J
Xu
Department of Cancer Genetics and Epigenetics and Beckman Research Institute of City of Hope, Duarte, California, USA; lzheng@coh.org.
Li
L
Zheng
Department of Cancer Genetics and Epigenetics and Beckman Research Institute of City of Hope, Duarte, California, USA; bshen@coh.org.
Binghui
B
Shen
D000595:Amino Acid Sequence; D000818:Animals; D004249:DNA Damage; D005260:Female; D005347:Fibroblasts; D045585:Flap Endonucleases / Q000235:genetics / Q000378:metabolism*; D059585:G1 Phase Cell Cycle Checkpoints / Q000502:physiology; D018507:Gene Expression Regulation, Developmental / Q000502:physiology*; D006321:Heart / Q000196:embryology / Q000254:growth & development*; D008297:Male; D051379:Mice; D018384:Oxidative Stress; D010100:Oxygen; D010766:Phosphorylation; D017354:Point Mutation
C572473:Fen1 protein, mouse; D045585:Flap Endonucleases; D010100:Oxygen
G1-phase arrest; dilated heart; flap endonuclease 1; p53 signaling
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