Pol θ-mediated end-joining uses microhomologies containing mismatches

Yuzhen Li, Ngoc K. Dang, Wei He, Mark Returan, Denisse Carvajal-Maldonado, Adele T. Guerin, Han Xu, Bin Liu and Richard D. Wood ()
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Yuzhen Li: MD Anderson Cancer Center
Ngoc K. Dang: MD Anderson Cancer Center
Wei He: MD Anderson Cancer Center
Mark Returan: MD Anderson Cancer Center
Denisse Carvajal-Maldonado: MD Anderson Cancer Center
Adele T. Guerin: MD Anderson Cancer Center
Han Xu: MD Anderson Cancer Center
Bin Liu: MD Anderson Cancer Center
Richard D. Wood: MD Anderson Cancer Center

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

Abstract: Abstract DNA polymerase theta (Pol θ) initiates repair of DNA double-strand breaks by pairing single strands at short “microhomologies”. It is important to understand microhomology selection, as some cancer cells rely on Pol θ for survival. Here, we investigate end-joining by purified human Pol θ, employing DNA sequencing of products generated from oligonucleotide libraries having diverse 3′ ends. Pol θ overwhelmingly selects short internal microhomologies found within 15 nucleotides of the terminus of single-stranded DNAs, restricting deletion size during end-joining. Significantly, we find that the selected microhomologies are usually interrupted by mismatches and that base pairing within 6 nucleotides of the 3′ end is important for determining microhomology choice. Bidirectional synthesis is not necessary to initiate end-joining. The preference for mismatched microhomologies suggests a revision of the definition of microhomology to account for the unique properties of Pol θ. This could advance the analysis of mutations in cancer genomes.

Date: 2025
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DOI: 10.1038/s41467-025-61258-3

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