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Mechanism of nucleotide discrimination by the translesion synthesis polymerase Rev1

Author

Listed:
  • Tyler M. Weaver

    (University of Kansas Medical Center
    University of Kansas Medical Center)

  • Timothy H. Click

    (Oklahoma State University)

  • Thu H. Khoang

    (University of Kansas Medical Center
    University of Kansas Medical Center)

  • M. Todd Washington

    (University of Iowa)

  • Pratul K. Agarwal

    (Oklahoma State University)

  • Bret D. Freudenthal

    (University of Kansas Medical Center
    University of Kansas Medical Center)

Abstract

Rev1 is a translesion DNA synthesis (TLS) polymerase involved in the bypass of adducted-guanine bases and abasic sites during DNA replication. During damage bypass, Rev1 utilizes a protein-template mechanism of DNA synthesis, where the templating DNA base is evicted from the Rev1 active site and replaced by an arginine side chain that preferentially binds incoming dCTP. Here, we utilize X-ray crystallography and molecular dynamics simulations to obtain structural insight into the dCTP specificity of Rev1. We show the Rev1 R324 protein-template forms sub-optimal hydrogen bonds with incoming dTTP, dGTP, and dATP that prevents Rev1 from adopting a catalytically competent conformation. Additionally, we show the Rev1 R324 protein-template forms optimal hydrogen bonds with incoming rCTP. However, the incoming rCTP adopts an altered sugar pucker, which prevents the formation of a catalytically competent Rev1 active site. This work provides novel insight into the mechanisms for nucleotide discrimination by the TLS polymerase Rev1.

Suggested Citation

  • Tyler M. Weaver & Timothy H. Click & Thu H. Khoang & M. Todd Washington & Pratul K. Agarwal & Bret D. Freudenthal, 2022. "Mechanism of nucleotide discrimination by the translesion synthesis polymerase Rev1," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-30577-0
    DOI: 10.1038/s41467-022-30577-0
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    References listed on IDEAS

    as
    1. Robert E. Johnson & M. Todd Washington & Lajos Haracska & Satya Prakash & Louise Prakash, 2000. "Eukaryotic polymerases ι and ζ act sequentially to bypass DNA lesions," Nature, Nature, vol. 406(6799), pages 1015-1019, August.
    2. Olga Rechkoblit & Alexander Kolbanovskiy & Hannah Landes & Nicholas E. Geacintov & Aneel K. Aggarwal, 2017. "Mechanism of error-free replication across benzo[a]pyrene stereoisomers by Rev1 DNA polymerase," Nature Communications, Nature, vol. 8(1), pages 1-10, December.
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