DNA polymerase delta Exo domain stabilizes mononucleotide microsatellites in human cells

Seijiro Shioi, Akiyoshi Shimamoto, Yingxia Song, Kyoko Hidaka, Maki Nakamura, Ayumi Take, Namiko Hayashi, Soichi Takiguchi, Ryosuke Fujikane, Masumi Hidaka, Shinya Oda, Yoshimichi Nakatsu

Research output: Contribution to journalArticlepeer-review

Abstract

In prokaryotes and yeasts, DNA polymerase proofreading (PPR) and DNA mismatch repair (MMR) cooperatively counteracts replication errors leading to repeat sequence destabilization (i.e. insertions/deletions of repeat units). However, PPR has not thus far been regarded as a mechanism stabilizing repeat sequences in higher eukaryotic cells. In a human cancer cell line, DLD-1, which carries mutations in both MSH6 and the Exo domain of POLD1, we previously observed that mononucleotide microsatellites were markedly destabilized whereas being stable in the simple MMR-defective backgrounds. In this study, we introduced the Exo domain mutation found in DLD-1 cells into MSH2-null HeLa cell clones, using CRISPR/Cas9 system. In the established Exo-/MMR-mutated HeLa clones, mononucleotide repeat sequences were remarkably destabilized as in DLD-1 cells. In contrast, dinucleotide microsatellites were readily destabilized in the parental MMR-deficient backgrounds, and the instability was not notably increased in the genome-edited HeLa clones. Here, we show an involvement of the Exo domain functions of DNA polymerase delta in mononucleotide repeat stabilization in human cells, which also suggests a possible role division between DNA polymerase and MMR in repeat maintenance in the human genome.

Original languageEnglish
Article number103216
JournalDNA Repair
Volume108
DOIs
Publication statusPublished - Dec 2021

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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