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

<div class='caption-title'>Base-pairing and specificity of 8-oxodGTP insertion.</div>
<div class='caption-title'>dGTP insertion opposite adenine and cytosine.</div>
<div class='caption-title'>8-oxodGTP insertion opposite At.</div>
Jamsen JA, Sassa A, Shock DD, Beard WA, Wilson SH
OpenAccess logo Nat Commun 12 2059 (2021)

Cited: 8 times
EuropePMC logo PMID: 33824325

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.

Articles - 7kt1 mentioned but not cited (1)

  1. Watching a double strand break repair polymerase insert a pro-mutagenic oxidized nucleotide. Jamsen JA, Sassa A, Shock DD, Beard WA, Wilson SH. Nat Commun 12 2059 (2021)


Reviews citing this publication (2)

  1. For the Better or for the Worse? The Effect of Manganese on the Activity of Eukaryotic DNA Polymerases. Balint E, Unk I. Int J Mol Sci 25 363 (2023)
  2. New insights into DNA polymerase mechanisms provided by time-lapse crystallography. Weaver TM, Washington MT, Freudenthal BD. Curr Opin Struct Biol 77 102465 (2022)

Articles citing this publication (5)

  1. Structural basis for proficient oxidized ribonucleotide insertion in double strand break repair. Jamsen JA, Sassa A, Perera L, Shock DD, Beard WA, Wilson SH. Nat Commun 12 5055 (2021)
  2. Watching right and wrong nucleotide insertion captures hidden polymerase fidelity checkpoints. Jamsen JA, Shock DD, Wilson SH. Nat Commun 13 3193 (2022)
  3. Processing oxidatively damaged bases at DNA strand breaks by APE1. Whitaker AM, Stark WJ, Freudenthal BD. Nucleic Acids Res 50 9521-9533 (2022)
  4. In crystallo observation of active site dynamics and transient metal ion binding within DNA polymerases. Chang C, Zhou G, Gao Y. Struct Dyn 10 034702 (2023)
  5. Structural Insight into Polymerase Mechanism via a Chiral Center Generated with a Single Selenium Atom. Qin T, Hu B, Zhao Q, Wang Y, Wang S, Luo D, Lyu J, Chen Y, Gan J, Huang Z. Int J Mol Sci 24 15758 (2023)


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