Mechanism of genome instability mediated by human DNA polymerase mu misincorporation

Miao Guo, Yina Wang, Yuyue Tang, Zijing Chen, Jinfeng Hou, Jingli Dai, Yudong Wang, Liangyan Wang, Hong Xu, Bing Tian, Yuejin Hua () and Ye Zhao ()
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Miao Guo: Institute of Biophysics, College of Life Sciences, Zhejiang University
Yina Wang: Institute of Biophysics, College of Life Sciences, Zhejiang University
Yuyue Tang: Institute of Biophysics, College of Life Sciences, Zhejiang University
Zijing Chen: Institute of Biophysics, College of Life Sciences, Zhejiang University
Jinfeng Hou: Institute of Biophysics, College of Life Sciences, Zhejiang University
Jingli Dai: Institute of Biophysics, College of Life Sciences, Zhejiang University
Yudong Wang: Institute of Biophysics, College of Life Sciences, Zhejiang University
Liangyan Wang: Institute of Biophysics, College of Life Sciences, Zhejiang University
Hong Xu: Institute of Biophysics, College of Life Sciences, Zhejiang University
Bing Tian: Institute of Biophysics, College of Life Sciences, Zhejiang University
Yuejin Hua: Institute of Biophysics, College of Life Sciences, Zhejiang University
Ye Zhao: Institute of Biophysics, College of Life Sciences, Zhejiang University

Nature Communications, 2021, vol. 12, issue 1, 1-9

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-24096-7

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