Replication studies of carboxymethylated DNA lesions in human cells

Nucleic Acids Research
Jun WuYinsheng Wang

Abstract

Metabolic activation of some N-nitroso compounds (NOCs), an important class of DNA damaging agents, can induce the carboxymethylation of nucleobases in DNA. Very little was previously known about how the carboxymethylated DNA lesions perturb DNA replication in human cells. Here, we investigated the effects of five carboxymethylated DNA lesions, i.e. O6-CMdG, N6-CMdA, N4-CMdC, N3-CMdT and O4-CMdT on the efficiency and fidelity of DNA replication in HEK293T human embryonic kidney cells. We found that, while neither N6-CMdA nor N4-CMdC blocked DNA replication or induced mutations, N3-CMdT, O4-CMdT and O6-CMdG moderately blocked DNA replication and induced substantial frequencies of T→A (81%), T→C (68%) and G→A (6.4%) mutations, respectively. In addition, our results revealed that CRISPR-Cas9-mediated depletion of Pol η resulted in significant drops in bypass efficiencies of N4-CMdC and N3-CMdT. Diminution in bypass efficiencies was also observed for N6-CMdA and O6-CMdG upon depletion of Pol κ, and for O6-CMdG upon removal of Pol ζ. Together, our study provided molecular-level insights into the impacts of the carboxymethylated DNA lesions on DNA replication in human cells, revealed the roles of individual translesion synthesis DNA ...Continue Reading

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Citations

Jan 19, 2019·The Journal of Biological Chemistry·Pengcheng WangYinsheng Wang
Aug 4, 2019·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Hannah R SternPenny J Beuning
Nov 30, 2019·Biochimica Et Biophysica Acta. Reviews on Cancer·Nina SeiwertJörg Fahrer
Mar 21, 2020·Journal of the American Chemical Society·Claudia M N AloisiShana J Sturla
Jun 2, 2021·Chemical Research in Toxicology·Susanne M GeisenShana J Sturla
Aug 20, 2020·Chemical Research in Toxicology·Yuhe KanYujian He
Jan 9, 2021·Chemical Research in Toxicology·Claudia M N AloisiShana J Sturla

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Methods Mentioned

BETA
electrophoresis
PCR

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