Polγ coordinates DNA synthesis and proofreading to ensure mitochondrial genome integrity

Joon Park, Geoffrey K. Herrmann, Patrick G. Mitchell, Michael B. Sherman, Y. Whitney Yin

Research output: Contribution to journalArticlepeer-review


Accurate replication of mitochondrial DNA (mtDNA) by DNA polymerase γ (Polγ) is essential for maintaining cellular energy supplies, metabolism, and cell cycle control. To illustrate the structural mechanism for Polγ coordinating polymerase (pol) and exonuclease (exo) activities to ensure rapid and accurate DNA synthesis, we determined four cryo-EM structures of Polγ captured after accurate or erroneous incorporation to a resolution of 2.4–3.0 Å. The structures show that Polγ employs a dual-checkpoint mechanism to sense nucleotide misincorporation and initiate proofreading. The transition from replication to error editing is accompanied by increased dynamics in both DNA and enzyme, in which the polymerase relaxes its processivity and the primer–template DNA unwinds, rotates, and backtracks to shuttle the mismatch-containing primer terminus 32 Å to the exo site for editing. Our structural and functional studies also provide a foundation for analyses of Polγ mutation-induced human diseases and aging.

Original languageEnglish (US)
Pages (from-to)812-823
Number of pages12
JournalNature Structural and Molecular Biology
Issue number6
StatePublished - Jun 2023
Externally publishedYes

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology


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