9BHA

Human DNA polymerase theta helicase domain dimer bound to DNA in the microhomology annealed conformation

9BHA の概要

• エントリーDOI: 10.2210/pdb9bha/pdb
• EMDBエントリー: 44538
• 分子名称: DNA polymerase theta, Stem-loop DNA with microhomology in the 3' overhang (2 entities in total)
• 機能のキーワード: dna repair, tmej, mmej, dna binding protein
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 233870.71

構造登録者

Zerio, C.J.,Lander, G.C. (登録日: 2024-04-19, 公開日: 2024-05-01, 最終更新日: 2025-03-12)

主引用文献

Zerio, C.J.,Bai, Y.,Sosa-Alvarado, B.A.,Guzi, T.,Lander, G.C.
Human polymerase theta helicase positions DNA microhomologies for double-strand break repair.
Nat.Struct.Mol.Biol., 2025

PubMed Abstract: DNA double-strand breaks occur daily in all human cells and must be repaired with high fidelity to minimize genomic instability. Deficiencies in high-fidelity DNA repair by homologous recombination lead to dependence on DNA polymerase θ, which identifies DNA microhomologies in 3' single-stranded DNA overhangs and anneals them to initiate error-prone double-strand break repair. The resulting genomic instability is associated with numerous cancers, thereby making this polymerase an attractive therapeutic target. However, despite the biomedical importance of polymerase θ, the molecular details of how it initiates DNA break repair remain unclear. Here, we present cryo-electron microscopy structures of the polymerase θ helicase domain bound to microhomology-containing DNA, revealing DNA-induced rearrangements of the helicase that enable DNA repair. Our structures show that DNA-bound helicase dimers facilitate a microhomology search that positions 3' single-stranded DNA ends in proximity to align complementary bases and anneal DNA microhomology. We characterize the molecular determinants that enable the helicase domain of polymerase θ to identify and pair DNA microhomologies to initiate mutagenic DNA repair, thereby providing insight into potentially targetable interactions for therapeutic interventions.

PubMed: 40021738
DOI: 10.1038/s41594-025-01514-8

実験手法

ELECTRON MICROSCOPY (3.5 Å)