Okazaki fragment maturation involves α-segment error editing by the mammalian FEN1/MutSα functional complex |
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| Authors: | Songbai Liu Guojun Lu Shafat Ali Wenpeng Liu Li Zheng Huifang Dai Hongzhi Li Hong Xu Yuejin Hua Yajing Zhou Janice Ortega Guo-Min Li Thomas A Kunkel Binghui Shen |
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| Institution: | 1. Colleges of Life Sciences and Agriculture and Biotechnology, Zhejiang University, Hangzhou, Zhejiang, China;2. Departments of Radiation Biology and Molecular Medicine, City of Hope National Medical Center and Beckman Research Institute, Duarte, CA, USA;3. Institute of Life Sciences, Jiangsu University, Zhen Jiang, Jiangsu, China;4. Graduate Center for Toxicology, Markey Cancer Center, University of Kentucky College of Medicine, Lexington, KY, USA;5. Genome Integrity and Structural Biology Laboratory, National Institute of Environmental Health Sciences, NIH, DHHS, Research Triangle Park, NC, USA |
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| Abstract: | During nuclear DNA replication, proofreading-deficient DNA polymerase α (Pol α) initiates Okazaki fragment synthesis with lower fidelity than bulk replication by proofreading-proficient Pol δ or Pol ε. Here, we provide evidence that the exonuclease activity of mammalian flap endonuclease (FEN1) excises Pol α replication errors in a MutSα-dependent, MutLα-independent mismatch repair process we call Pol α-segment error editing (AEE). We show that MSH2 interacts with FEN1 and facilitates its nuclease activity to remove mismatches near the 5′ ends of DNA substrates. Mouse cells and mice encoding FEN1 mutations display AEE deficiency, a strong mutator phenotype, enhanced cellular transformation, and increased cancer susceptibility. The results identify a novel role for FEN1 in a specialized mismatch repair pathway and a new cancer etiological mechanism. |
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| Keywords: | DNA mismatch repair flap endonuclease 1 MutSα Okazaki fragment maturation α -segment error editing |
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