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Mechanism of genome instability mediated by human DNA polymerase mu misincorporation

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  • Miao Guo

    (Institute of Biophysics, College of Life Sciences, Zhejiang University
    MOE Key Laboratory of Biosystems Homeostasis & Protection, Zhejiang University)

  • Yina Wang

    (Institute of Biophysics, College of Life Sciences, Zhejiang University
    MOE Key Laboratory of Biosystems Homeostasis & Protection, Zhejiang University)

  • Yuyue Tang

    (Institute of Biophysics, College of Life Sciences, Zhejiang University
    MOE Key Laboratory of Biosystems Homeostasis & Protection, Zhejiang University)

  • Zijing Chen

    (Institute of Biophysics, College of Life Sciences, Zhejiang University
    MOE Key Laboratory of Biosystems Homeostasis & Protection, Zhejiang University)

  • Jinfeng Hou

    (Institute of Biophysics, College of Life Sciences, Zhejiang University
    MOE Key Laboratory of Biosystems Homeostasis & Protection, Zhejiang University)

  • Jingli Dai

    (Institute of Biophysics, College of Life Sciences, Zhejiang University
    MOE Key Laboratory of Biosystems Homeostasis & Protection, Zhejiang University)

  • Yudong Wang

    (Institute of Biophysics, College of Life Sciences, Zhejiang University
    MOE Key Laboratory of Biosystems Homeostasis & Protection, Zhejiang University)

  • Liangyan Wang

    (Institute of Biophysics, College of Life Sciences, Zhejiang University
    MOE Key Laboratory of Biosystems Homeostasis & Protection, Zhejiang University)

  • Hong Xu

    (Institute of Biophysics, College of Life Sciences, Zhejiang University
    MOE Key Laboratory of Biosystems Homeostasis & Protection, Zhejiang University)

  • Bing Tian

    (Institute of Biophysics, College of Life Sciences, Zhejiang University
    MOE Key Laboratory of Biosystems Homeostasis & Protection, Zhejiang University)

  • Yuejin Hua

    (Institute of Biophysics, College of Life Sciences, Zhejiang University
    MOE Key Laboratory of Biosystems Homeostasis & Protection, Zhejiang University)

  • Ye Zhao

    (Institute of Biophysics, College of Life Sciences, Zhejiang University
    MOE Key Laboratory of Biosystems Homeostasis & Protection, Zhejiang University)

Abstract

Pol μ is capable of performing gap-filling repair synthesis in the nonhomologous end joining (NHEJ) pathway. Together with DNA ligase, misincorporation of dGTP opposite the templating T by Pol μ results in a promutagenic T:G mispair, leading to genomic instability. Here, crystal structures and kinetics of Pol μ substituting dGTP for dATP on gapped DNA substrates containing templating T were determined and compared. Pol μ is highly mutagenic on a 2-nt gapped DNA substrate, with T:dGTP base pairing at the 3ʹ end of the gap. Two residues (Lys438 and Gln441) interact with T:dGTP and fine tune the active site microenvironments. The in-crystal misincorporation reaction of Pol μ revealed an unexpected second dGTP in the active site, suggesting its potential mutagenic role among human X family polymerases in NHEJ.

Suggested Citation

  • Miao Guo & Yina Wang & Yuyue Tang & Zijing Chen & Jinfeng Hou & Jingli Dai & Yudong Wang & Liangyan Wang & Hong Xu & Bing Tian & Yuejin Hua & Ye Zhao, 2021. "Mechanism of genome instability mediated by human DNA polymerase mu misincorporation," Nature Communications, Nature, vol. 12(1), pages 1-9, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-24096-7
    DOI: 10.1038/s41467-021-24096-7
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    Cited by:

    1. Qun Tang & Mitchell Gulkis & Robert McKenna & Melike Çağlayan, 2022. "Structures of LIG1 that engage with mutagenic mismatches inserted by polβ in base excision repair," Nature Communications, Nature, vol. 13(1), pages 1-11, December.

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