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Structural basis for Polθ-helicase DNA binding and microhomology-mediated end-joining
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Structural basis for Polθ-helicase DNA binding and microhomology-mediated end-joining
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Journal Article
Structural basis for Polθ-helicase DNA binding and microhomology-mediated end-joining
2025
Overview
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 different 3′-ssDNA overhangs. 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′-ssDNA 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.
DNA polymerase theta (Polθ) plays central roles in microhomology-mediated end joining (MMEJ) DNA damage repair. Here, the authors determine a series of structures of Polθ helicase domain during the MMEJ, revealing key conformational changes for DNA binding, microhomology search, and annealing.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 631/67
/ 82/29
/ 82/83
/ Binding
/ DNA
/ DNA Helicases - ultrastructure
/ DNA, Single-Stranded - chemistry
/ DNA, Single-Stranded - metabolism
/ DNA-Directed DNA Polymerase - chemistry
/ DNA-Directed DNA Polymerase - genetics
/ DNA-Directed DNA Polymerase - metabolism
/ DNA-Directed DNA Polymerase - ultrastructure
/ Humanities and Social Sciences
/ Humans
/ Science
/ Yeast
