Double-strand break repair pathways differentially affect processing and transduction by dual AAV vectors

Anna C. Maurer (acmaurer@umich.edu), Brian Benyamini, Oscar N. Whitney, Vinson B. Fan, Claudia Cattoglio, Djem U. Kissiov, Gina M. Dailey, Xavier Darzacq, Matthew D. Weitzman and Robert Tjian
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Anna C. Maurer: University of California
Brian Benyamini: University of California
Oscar N. Whitney: University of California
Vinson B. Fan: University of California
Claudia Cattoglio: University of California
Djem U. Kissiov: University of California
Gina M. Dailey: University of California
Xavier Darzacq: University of California
Matthew D. Weitzman: University of Pennsylvania Perelman School of Medicine and the Children’s Hospital of Philadelphia
Robert Tjian: University of California

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

Abstract: Abstract Recombinant adeno-associated viral vectors (rAAV) are a powerful tool for gene delivery but have a limited DNA carrying capacity. Efforts to expand this genetic payload have focused on engineering the vector components, such as dual trans-splicing vectors which double the delivery size by exploiting the natural concatenation of rAAV genomes in host nuclei. We hypothesized that inefficient dual vector transduction could be improved by modulating host factors which affect concatenation. Since factors mediating concatenation are not well defined, we performed a genome-wide screen to identify host cell regulators. We discover that Homologous Recombination (HR) is inhibitory to dual vector transduction. We demonstrate that depletion or inhibition of HR factors BRCA1 and Rad51 significantly increase reconstitution of a large split transgene by increasing both concatenation and expression from rAAVs. Our results define roles for DNA damage repair in rAAV transduction and highlight the potential for pharmacological intervention to increase genetic payload of rAAV vectors.

Date: 2025
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DOI: 10.1038/s41467-025-56738-5

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