Enhancing homology-directed repair efficiency with HDR-boosting modular ssDNA donor

Ying-Ying Jin, Peng Zhang, Le-Le Liu, Xiang Zhao, Xiao-Qing Hu, Si-Zhe Liu, Ze-Kun Li, Qian Liu, Jian-Qiao Wang, Hao De-Long, Zhu-Qin Zhang, Hou-Zao Chen () and Liu De-Pei ()
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Ying-Ying Jin: Chinese Academy of Medical Sciences & Peking Union Medical College
Peng Zhang: Chinese Academy of Medical Sciences & Peking Union Medical College
Le-Le Liu: Chinese Academy of Medical Sciences & Peking Union Medical College
Xiang Zhao: Chinese Academy of Medical Sciences & Peking Union Medical College
Xiao-Qing Hu: Chinese Academy of Medical Sciences & Peking Union Medical College
Si-Zhe Liu: Chinese Academy of Medical Sciences & Peking Union Medical College
Ze-Kun Li: Chinese Academy of Medical Sciences & Peking Union Medical College
Qian Liu: Chinese Academy of Medical Sciences & Peking Union Medical College
Jian-Qiao Wang: Chinese Academy of Medical Sciences & Peking Union Medical College
Hao De-Long: Chinese Academy of Medical Sciences & Peking Union Medical College
Zhu-Qin Zhang: Chinese Academy of Medical Sciences & Peking Union Medical College
Hou-Zao Chen: Chinese Academy of Medical Sciences & Peking Union Medical College
Liu De-Pei: Chinese Academy of Medical Sciences & Peking Union Medical College

Nature Communications, 2024, vol. 15, issue 1, 1-14

Abstract: Abstract Despite the potential of small molecules and recombinant proteins to enhance the efficiency of homology-directed repair (HDR), single-stranded DNA (ssDNA) donors, as currently designed and chemically modified, remain suboptimal for precise gene editing. Here, we screen the biased ssDNA binding sequences of DNA repair-related proteins and engineer RAD51-preferred sequences into HDR-boosting modules for ssDNA donors. Donors with these modules exhibit an augmented affinity for RAD51, thereby enhancing HDR efficiency across various genomic loci and cell types when cooperated with Cas9, nCas9, and Cas12a. By combining with an inhibitor of non-homologous end joining (NHEJ) or the HDRobust strategy, these modular ssDNA donors achieve up to 90.03% (median 74.81%) HDR efficiency. The HDR-boosting modules targeting an endogenous protein enable a chemical modification-free strategy to improve the efficacy of ssDNA donors for precise gene editing.

Date: 2024
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DOI: 10.1038/s41467-024-50788-x

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