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Extrinsic proofreading.

Zhi-Xiong Zhou1, Thomas A Kunkel1

  • 1Genome Integrity Structural Biology Laboratory, National Institute of Environmental Health Sciences, NIH, DHHS, Research Triangle Park, NC 27709, USA.

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|July 19, 2022
PubMed
Summary
This summary is machine-generated.

DNA polymerases α, δ, and ε ensure accurate DNA replication through proofreading. This review highlights two proofreading mechanisms: intrinsic and extrinsic, with extrinsic proofreading by DNA polymerase δ significantly enhancing nuclear DNA replication fidelity.

Keywords:
Base substitutionsDNA polymeraseGenome stabilityMismatchesProofreadingReplication fidelity

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Area of Science:

  • Molecular Biology
  • Genetics
  • Biochemistry

Background:

  • Eukaryotic nuclear DNA replication relies on high fidelity to maintain genome integrity.
  • Three primary mechanisms contribute to DNA replication fidelity: accurate nucleotide incorporation, proofreading by DNA polymerases, and DNA mismatch repair.
  • DNA polymerases α, δ, and ε are the main replicases involved in nuclear DNA synthesis.

Purpose of the Study:

  • To review evidence supporting the hypothesis that DNA polymerase proofreading operates via two distinct mechanisms.
  • To examine the role of intrinsic and extrinsic proofreading in DNA replication fidelity.
  • To discuss the implications of extrinsic proofreading for evolution and disease.

Main Methods:

  • Review of existing scientific literature and evidence.
  • Analysis of mechanisms of DNA polymerase proofreading (intrinsic and extrinsic).
  • Comparison of the efficiency of different proofreading strategies.

Main Results:

  • Primer terminal mismatches can be excised via 'intrinsic' proofreading, involving direct transfer to the exonuclease site without enzyme dissociation.
  • 'Extrinsic' proofreading, mediated by DNA polymerase δ, allows for mismatch removal after initial abandonment by any of the three replicases.
  • Extrinsic proofreading by DNA polymerase δ substantially increases the fidelity of nuclear DNA replication.

Conclusions:

  • Proofreading by DNA polymerases is a critical process for maintaining genome stability.
  • Extrinsic proofreading by DNA polymerase δ plays a significant role in enhancing DNA replication fidelity.
  • Understanding these proofreading mechanisms offers insights into evolutionary processes and the origins of genetic diseases.