Okazaki fragment maturation involves α-segment error editing by the mammalian FEN1/MutSα functional complex

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

Research output: Contribution to journalArticle

17 Scopus citations

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. Synopsis Okazaki fragment synthesis during eukaryotic DNA replication is initiated by proofreading-deficient DNA polymerase α, requiring a dedicated repair process during Okazaki fragment maturation. This Pol alpha-segment error editing (AEE) involves the exonuclease activity of flap endonuclease (FEN1) in cooperation with MutSα mismatch repair protein. MutSα recognizes mismatches near the 5′ end of the DNA nick left after RNA primer flap cleavage. MutSα interacts with FEN1 and stimulates mismatch removal by FEN1 exonuclease activity. Defects in AEE lead to increased genome instability and cancer susceptibility. The key role of proofreading-deficient DNA polymerase α in initiating Okazaki fragment synthesis requires mismatch removal by a dedicated DNA repair process involving mammalian flap endonuclease.

Original languageEnglish (US)
Pages (from-to)1829-1843
Number of pages15
JournalEMBO Journal
Volume34
Issue number13
DOIs
StatePublished - Jul 2 2015

Keywords

  • DNA mismatch repair
  • flap endonuclease 1
  • MutSα
  • Okazaki fragment maturation
  • α-segment error editing

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

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    Liu, S., Lu, G., Ali, S., Liu, W., Zheng, L., Dai, H., Li, H., Xu, H., Hua, Y., Zhou, Y., Ortega, J., Li, G. M., Kunkel, T. A., & Shen, B. (2015). Okazaki fragment maturation involves α-segment error editing by the mammalian FEN1/MutSα functional complex. EMBO Journal, 34(13), 1829-1843. https://doi.org/10.15252/embj.201489865