Structural basis for Polθ-helicase DNA binding and microhomology-mediated end-joining

Fumiaki Ito, Ziyuan Li, Leonid Minakhin, Htet A. Khant, Richard T. Pomerantz () and Xiaojiang S. Chen ()
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Fumiaki Ito: University of Southern California
Ziyuan Li: University of Southern California
Leonid Minakhin: Thomas Jefferson University
Htet A. Khant: University of Southern California
Richard T. Pomerantz: Thomas Jefferson University
Xiaojiang S. Chen: University of Southern California

Nature Communications, 2025, vol. 16, issue 1, 1-14

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-58441-x

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