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Mechanism of genome instability mediated by human DNA polymerase mu misincorporation.

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 3' 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.

SUBMITTER: Guo M

PROVIDER: S-EPMC8213813 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature

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Mechanism of genome instability mediated by human DNA polymerase mu misincorporation.

Guo Miao M Wang Yina Y Tang Yuyue Y Chen Zijing Z Hou Jinfeng J Dai Jingli J Wang Yudong Y Wang Liangyan L Xu Hong H Tian Bing B Hua Yuejin Y Zhao Ye Y

Nature communications 20210618 1

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 pairin ...[more]

PMID: 34145298

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