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-Structure paper
タイトル | Structural Basis for Polθ-Helicase DNA Binding and Microhomology-Mediated End-Joining. |
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ジャーナル・号・ページ | bioRxiv, Year 2024 |
掲載日 | 2024年6月7日 |
著者 | Fumiaki Ito / Ziyuan Li / Leonid Minakhin / Htet A Khant / Richard T Pomerantz / Xiaojiang S Chen / |
PubMed 要旨 | DNA double-strand breaks (DSBs) present a critical threat to genomic integrity, often precipitating genomic instability and oncogenesis. Repair of DSBs predominantly occurs through homologous ...DNA double-strand breaks (DSBs) present a critical threat to genomic integrity, often precipitating genomic instability and oncogenesis. Repair of DSBs predominantly occurs through homologous recombination (HR) and non-homologous end joining (NHEJ). In HR-deficient cells, DNA polymerase theta (Polθ) becomes critical for DSB repair via microhomology-mediated end joining (MMEJ), also termed theta-mediated end joining (TMEJ). Thus, Polθ is synthetically lethal with BRCA1/2 and other HR factors, underscoring its potential as a therapeutic target in HR-deficient cancers. However, the molecular mechanisms governing Polθ-mediated MMEJ remain poorly understood. Here we present a series of cryo-electron microscopy structures of the Polθ helicase domain (Polθ-hel) in complex with DNA containing 3'-overhang. The structures reveal the sequential conformations adopted by Polθ-hel during the critical phases of DNA binding, microhomology searching, and microhomology annealing. The stepwise conformational changes within the Polθ-hel subdomains and its functional dimeric state are pivotal for aligning the 3'-overhangs, facilitating the microhomology search and subsequent annealing necessary for DSB repair via MMEJ. Our findings illustrate the essential molecular switches within Polθ-hel that orchestrate the MMEJ process in DSB repair, laying the groundwork for the development of targeted therapies against the Polθ-hel. |
リンク | bioRxiv / PubMed:38895274 / PubMed Central |
手法 | EM (単粒子) |
解像度 | 3.1 - 3.8 Å |
構造データ | EMDB-43706, PDB-8w0a: EMDB-43816, PDB-9asj: EMDB-43817, PDB-9ask: EMDB-43818, PDB-9asl: EMDB-45217: Human DNA polymerase theta helicase domain in microhomology annealed state 1, dimer form EMDB-45218, PDB-9c5q: |
化合物 | ChemComp-ANP: |
由来 |
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キーワード | TRANSFERASE/DNA / DNA repair / helicase / ATPase / TRANSFERASE-DNA complex / TRANSFERASE / DNA BINDING PROTEIN |