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Spontaneous mutagenesis in human cells is controlled by REV1-Polymerase z and PRIMPOL

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CELL REPORTS
卷 42, 期 8, 页码 -

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CELL PRESS
DOI: 10.1016/j.celrep.2023.112887

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Translesion DNA synthesis (TLS) using specialized DNA polymerases facilitates replication over damaged or difficult-to-replicate templates. Investigating three main TLS control mechanisms, REV1 and PCNA ubiquitylation recruit TLS polymerases while PRIMPOL creates post-replicative gaps. Whole-genome sequencing of human RPE-1 cell clones reveals REV1 and Polymerase z as responsible for base substitution mutagenesis resembling homologous recombination deficiency, while PRIMPOL-/- cells show reduced component resembling oxidative mutagenesis. Small deletions in short repeats appear in REV1-/-PCNAK164R/K164R double mutants, revealing an alternative TLS mechanism. REV1-/- and REV3L-/- mutants exhibit 500-5,000 bp deletions, and REV1-/- PRIMPOL-/- cells show chromosomal instability. TLS protects against deletions and large rearrangements but contributes to spontaneous base substitutions.
Translesion DNA synthesis (TLS) facilitates replication over damaged or difficult-to-replicate templates by employing specialized DNA polymerases. We investigate the effect on spontaneous mutagenesis of three main TLS control mechanisms: REV1 and PCNA ubiquitylation that recruit TLS polymerases and PRIMPOL that creates post-replicative gaps. Using whole-genome sequencing of cultured human RPE-1 cell clones, we find that REV1 and Polymerase z are wholly responsible for one component of base substitution mutagenesis that resembles homologous recombination deficiency, whereas the remaining component that approximates oxidative mutagenesis is reduced in PRIMPOL-/- cells. Small deletions in short repeats appear in REV1-/-PCNAK164R/K164R double mutants, revealing an alternative TLS mechanism. Also, 500-5,000 bp deletions appear in REV1-/- and REV3L-/- mutants, and chromosomal instability is detectable in REV1-/- PRIMPOL-/- cells. Our results indicate that TLS protects the genome from deletions and large rearrangements at the expense of being responsible for the majority of spontaneous base substitutions.

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