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Structure paper

タイトル	Polγ coordinates DNA synthesis and proofreading to ensure mitochondrial genome integrity.
ジャーナル・号・ページ	Nat Struct Mol Biol, Vol. 30, Issue 6, Page 812-823, Year 2023
掲載日	2023年5月18日
著者	Joon Park / Geoffrey K Herrmann / Patrick G Mitchell / Michael B Sherman / Y Whitney Yin /
PubMed 要旨	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 ...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.
リンク	Nat Struct Mol Biol / PubMed:37202477 / PubMed Central
手法	EM (単粒子)
解像度	2.46 - 3.04 Å
構造データ	27154 8d33 EMDB-27154, PDB-8d33: Human mitochondrial DNA polymerase gamma ternary complex with GC basepair 手法: EM (単粒子) / 解像度: 2.46 Å 27155 8d37 EMDB-27155, PDB-8d37: Human mitochondrial DNA polymerase gamma ternary complex with GT basepair in replication conformer 手法: EM (単粒子) / 解像度: 2.65 Å 27163 8d3r EMDB-27163, PDB-8d3r: Human mitochondrial DNA polymerase gamma ternary complex with GT basepair in intermediate conformer 手法: EM (単粒子) / 解像度: 3.04 Å EMDB-27169: Human mitochondrial DNA polymerase gamma ternary complex with GT basepair in editing conformer (consensus) 手法: EM (単粒子) / 解像度: 2.91 Å EMDB-27170: Human mitochondrial DNA polymerase gamma ternary complex with GT basepair in editing conformer (local refinement of subunit A and primer/template DNA) 手法: EM (単粒子) / 解像度: 2.76 Å EMDB-27171: Human mitochondrial DNA polymerase gamma ternary complex with GT basepair in editing conformer (local refinement of subunit B) 手法: EM (単粒子) / 解像度: 2.76 Å 27172 8d42 EMDB-27172, PDB-8d42: Human mitochondrial DNA polymerase gamma ternary complex with GT basepair in editing conformer (composite) 手法: EM (単粒子) / 解像度: 2.91 Å
化合物	ChemComp-CA: Unknown entry / カルシウムジカチオン ChemComp-DCP: 2'-DEOXYCYTIDINE-5'-TRIPHOSPHATE / dCTP
由来	homo sapiens (ヒト) synthetic construct (人工物)
キーワード	TRANSFERASE/DNA / DNA-binding protein / DNA polymerase / TRANSFERASE-DNA complex