Okazaki fragment maturation involves α-segment error editing by the mammalian FEN1/MutSα functional complex.
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.
Colleges of Life Sciences and Agriculture and Biotechnology, Zhejiang University, Hangzhou Zhejiang, China Departments of Radiation Biology and Molecular Medicine, City of Hope National Medical Center and Beckman Research Institute, Duarte, CA, USA.
Songbai
S
Liu
Departments of Radiation Biology and Molecular Medicine, City of Hope National Medical Center and Beckman Research Institute, Duarte, CA, USA.
Guojun
G
Lu
Departments of Radiation Biology and Molecular Medicine, City of Hope National Medical Center and Beckman Research Institute, Duarte, CA, USA.
Shafat
S
Ali
Colleges of Life Sciences and Agriculture and Biotechnology, Zhejiang University, Hangzhou Zhejiang, China Departments of Radiation Biology and Molecular Medicine, City of Hope National Medical Center and Beckman Research Institute, Duarte, CA, USA.
Wenpeng
W
Liu
Departments of Radiation Biology and Molecular Medicine, City of Hope National Medical Center and Beckman Research Institute, Duarte, CA, USA.
Li
L
Zheng
Departments of Radiation Biology and Molecular Medicine, City of Hope National Medical Center and Beckman Research Institute, Duarte, CA, USA.
Huifang
H
Dai
Departments of Radiation Biology and Molecular Medicine, City of Hope National Medical Center and Beckman Research Institute, Duarte, CA, USA.
Hongzhi
H
Li
Colleges of Life Sciences and Agriculture and Biotechnology, Zhejiang University, Hangzhou Zhejiang, China.
Hong
H
Xu
Colleges of Life Sciences and Agriculture and Biotechnology, Zhejiang University, Hangzhou Zhejiang, China.
Yuejin
Y
Hua
Institute of Life Sciences, Jiangsu University, Zhen Jiang Jiangsu, China.
Yajing
Y
Zhou
Graduate Center for Toxicology, Markey Cancer Center, University of Kentucky College of Medicine, Lexington, KY, USA.
Janice
J
Ortega
Graduate Center for Toxicology, Markey Cancer Center, University of Kentucky College of Medicine, Lexington, KY, USA.
Guo-Min
GM
Li
Genome Integrity and Structural Biology Laboratory, National Institute of Environmental Health Sciences, NIH, DHHS, Research Triangle Park, NC, USA.
Thomas A
TA
Kunkel
Departments of Radiation Biology and Molecular Medicine, City of Hope National Medical Center and Beckman Research Institute, Duarte, CA, USA bshen@coh.org.
Binghui
B
Shen
D000818:Animals; D002478:Cells, Cultured; D004247:DNA / Q000378:metabolism*; D053843:DNA Mismatch Repair / Q000235:genetics; D004256:DNA Polymerase I / Q000378:metabolism*; D004261:DNA Replication / Q000235:genetics; D004622:Embryo, Mammalian; D005260:Female; D045585:Flap Endonucleases / Q000145:classification / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D051719:MutS DNA Mismatch-Binding Protein / Q000235:genetics / Q000378:metabolism*; D012441:Saccharomyces cerevisiae
C022262:Okazaki fragments; D004247:DNA; D004256:DNA Polymerase I; D045585:Flap Endonucleases; D051719:MutS DNA Mismatch-Binding Protein
DNA mismatch repair; MutSα; Okazaki fragment maturation; flap endonuclease 1; α‐segment error editing