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Distinctive roles of translesion polymerases DinB1 and DnaE2 in diversification of the mycobacterial genome through substitution and frameshift mutagenesis

Author

Listed:
  • Pierre Dupuy

    (Sloan Kettering Institute)

  • Shreya Ghosh

    (Sloan-Kettering Institute)

  • Oyindamola Adefisayo

    (Sloan Kettering Institute
    Weill Cornell Graduate School)

  • John Buglino

    (Sloan Kettering Institute)

  • Stewart Shuman

    (Sloan-Kettering Institute)

  • Michael S. Glickman

    (Sloan Kettering Institute
    Weill Cornell Graduate School)

Abstract

Antibiotic resistance of Mycobacterium tuberculosis is exclusively a consequence of chromosomal mutations. Translesion synthesis (TLS) is a widely conserved mechanism of DNA damage tolerance and mutagenesis, executed by translesion polymerases such as DinBs. In mycobacteria, DnaE2 is the only known agent of TLS and the role of DinB polymerases is unknown. Here we demonstrate that, when overexpressed, DinB1 promotes missense mutations conferring resistance to rifampicin, with a mutational signature distinct from that of DnaE2, and abets insertion and deletion frameshift mutagenesis in homo-oligonucleotide runs. DinB1 is the primary mediator of spontaneous −1 frameshift mutations in homo-oligonucleotide runs whereas DnaE2 and DinBs are redundant in DNA damage-induced −1 frameshift mutagenesis. These results highlight DinB1 and DnaE2 as drivers of mycobacterial genome diversification with relevance to antimicrobial resistance and host adaptation.

Suggested Citation

  • Pierre Dupuy & Shreya Ghosh & Oyindamola Adefisayo & John Buglino & Stewart Shuman & Michael S. Glickman, 2022. "Distinctive roles of translesion polymerases DinB1 and DnaE2 in diversification of the mycobacterial genome through substitution and frameshift mutagenesis," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-32022-8
    DOI: 10.1038/s41467-022-32022-8
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