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Watching a double strand break repair polymerase insert a pro-mutagenic oxidized nucleotide

Author

Listed:
  • Joonas A. Jamsen

    (National Institute of Environmental Health Sciences, National Institutes of Health)

  • Akira Sassa

    (Chiba University)

  • David D. Shock

    (National Institute of Environmental Health Sciences, National Institutes of Health)

  • William A. Beard

    (National Institute of Environmental Health Sciences, National Institutes of Health)

  • Samuel H. Wilson

    (National Institute of Environmental Health Sciences, National Institutes of Health)

Abstract

Oxidized dGTP (8-oxo-7,8-dihydro-2´-deoxyguanosine triphosphate, 8-oxodGTP) insertion by DNA polymerases strongly promotes cancer and human disease. How DNA polymerases discriminate against oxidized and undamaged nucleotides, especially in error-prone double strand break (DSB) repair, is poorly understood. High-resolution time-lapse X-ray crystallography snapshots of DSB repair polymerase μ undergoing DNA synthesis reveal that a third active site metal promotes insertion of oxidized and undamaged dGTP in the canonical anti-conformation opposite template cytosine. The product metal bridged O8 with product oxygens, and was not observed in the syn-conformation opposite template adenine (At). Rotation of At into the syn-conformation enabled undamaged dGTP misinsertion. Exploiting metal and substrate dynamics in a rigid active site allows 8-oxodGTP to circumvent polymerase fidelity safeguards to promote pro-mutagenic double strand break repair.

Suggested Citation

  • Joonas A. Jamsen & Akira Sassa & David D. Shock & William A. Beard & Samuel H. Wilson, 2021. "Watching a double strand break repair polymerase insert a pro-mutagenic oxidized nucleotide," Nature Communications, Nature, vol. 12(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-21354-6
    DOI: 10.1038/s41467-021-21354-6
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