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Okazaki fragment maturation involves ?-segment error editing by the mammalian FEN1/MutS? functional complex.

ABSTRACT: During nuclear DNA replication, proofreading-deficient DNA polymerase ? (Pol ?) initiates Okazaki fragment synthesis with lower fidelity than bulk replication by proofreading-proficient Pol ? or Pol ?. Here, we provide evidence that the exonuclease activity of mammalian flap endonuclease (FEN1) excises Pol ? replication errors in a MutS?-dependent, MutL?-independent mismatch repair process we call Pol ?-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.

SUBMITTER: Liu S 

PROVIDER: S-EPMC4516434 | biostudies-literature | 2015 Jul

REPOSITORIES: biostudies-literature

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

Liu Songbai S   Lu Guojun G   Ali Shafat S   Liu Wenpeng W   Zheng Li L   Dai Huifang H   Li Hongzhi H   Xu Hong H   Hua Yuejin Y   Zhou Yajing Y   Ortega Janice J   Li Guo-Min GM   Kunkel Thomas A TA   Shen Binghui B  

The EMBO journal 20150428 13

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 nuclea  ...[more]

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