12SL

Structure of a Strand-Displacement Complex of Human Mitochondrial DNA Polymerase Gamma

Summary for 12SL

• Entry DOI: 10.2210/pdb12sl/pdb
• EMDB information: 76732
• Descriptor: DNA polymerase subunit gamma-1, DNA polymerase subunit gamma-2, mitochondrial, primer DNA, ... (7 entities in total)
• Functional Keywords: mitochondrial dna polymerase gamma, polg, dna strand displacement, replication
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 5
• Total formula weight: 263714.87

Authors

Nayak, A.R.,Sokolova, V.O.,Temiakov, D. (deposition date: 2026-04-16, release date: 2026-10-07)

Primary citation

Sokolova, V.,Buchel, G.,Strock, S.,Nayak, A.R.,Temiakov, D.
Molecular and structural basis for replication initiation and strand separation by human mitochondrial DNA polymerase gamma.
Nucleic Acids Res., 54:-, 2026

PubMed Abstract: Defects in human mitochondrial DNA (mtDNA) replication can lead to somatic mutations associated with a range of devastating mitochondrial diseases. However, the molecular mechanisms governing the earliest steps of mtDNA replication and their fidelity remain poorly understood. Here, we found that DNA polymerase gamma (Polγ) forms stable complexes with RNA-DNA primer-template substrates, exhibiting greater stability and lower misincorporation than on DNA-primed substrates. Structural analysis revealed that Polγ interacts with the 2'-OH groups of ribose within the first four nucleotides of the primer, explaining the stability of complexes that utilize RNA primers. Although Polγ requires TWINKLE to extend RNA primers, its intrinsic strand-displacement activity allows it to extend DNA primers independently. Structural data further show that the strand-separation mechanism in human Polγ is distinct from that of its yeast paralog, Mip1, and involves previously unresolved elements-the catcher and a GP loop in the exonuclease domain-that support intrinsic strand-displacement synthesis by Polγ. Structure-guided mutagenesis of elements involved in strand separation supports these structural observations. Together, our study provides mechanistic insight into mtDNA replication initiation and strand separation and has implications for understanding the molecular basis of mitochondrial disease.

PubMed: 42788360
DOI: 10.1093/nar/gkag925

Experimental method

ELECTRON MICROSCOPY (2.93 Å)