Characterizing and controlling CRISPR repair outcomes in nondividing human cells

Gokul N. Ramadoss, Samali J. Namaganda, Manasi M. Kumar, Jennifer R. Hamilton, Rohit Sharma, Karena G. Chow, Luke A. Workley, Bria L. Macklin, Mengyuan Sun, Alvin S. Ha, Jia-Cheng Liu, Christof Fellmann, Hannah L. Watry, Philip H. Dierks, Rudra S. Bose, Julianne Jin, Barbara S. Perez, Cindy R. Sandoval Espinoza, Madeline P. Matia, Serena H. Lu, Luke M. Judge, Brian R. Shy, Andre Nussenzweig, Britt Adamson, Niren Murthy, Jennifer A. Doudna, Martin Kampmann and Bruce R. Conklin ()
Additional contact information
Gokul N. Ramadoss: Gladstone Institutes
Samali J. Namaganda: Gladstone Institutes
Manasi M. Kumar: Gladstone Institutes
Jennifer R. Hamilton: University of California
Rohit Sharma: University of California
Karena G. Chow: Gladstone Institutes
Luke A. Workley: Gladstone Institutes
Bria L. Macklin: Gladstone Institutes
Mengyuan Sun: Gladstone Institutes
Alvin S. Ha: Gladstone Institutes
Jia-Cheng Liu: NIH
Christof Fellmann: Gladstone Institutes
Hannah L. Watry: Gladstone Institutes
Philip H. Dierks: Gladstone Institutes
Rudra S. Bose: University of California
Julianne Jin: University of California
Barbara S. Perez: University of California
Cindy R. Sandoval Espinoza: University of California
Madeline P. Matia: Gladstone Institutes
Serena H. Lu: Gladstone Institutes
Luke M. Judge: Gladstone Institutes
Brian R. Shy: Gladstone Institutes
Andre Nussenzweig: NIH
Britt Adamson: Princeton University
Niren Murthy: University of California
Jennifer A. Doudna: Gladstone Institutes
Martin Kampmann: University of California
Bruce R. Conklin: Gladstone Institutes

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

Abstract: Abstract Genome editing is poised to revolutionize treatment of genetic diseases, but poor understanding and control of DNA repair outcomes hinders its therapeutic potential. DNA repair is especially understudied in nondividing cells like neurons, limiting the efficiency and precision of genome editing in many clinically relevant tissues. Here, we address this barrier by using induced pluripotent stem cells (iPSCs) and iPSC-derived neurons to examine how postmitotic human neurons repair Cas9-induced DNA damage. CRISPR editing outcomes differ dramatically in neurons compared to genetically identical dividing cells: neurons take longer to fully resolve this damage, and upregulate non-canonical DNA repair factors in the process. Manipulating this response with chemical or genetic perturbations allows us to direct DNA repair toward desired editing outcomes in nondividing human neurons, cardiomyocytes, and primary T cells. By studying DNA repair in clinically relevant cells, we reveal unforeseen challenges and opportunities for precise therapeutic editing.

Date: 2025
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DOI: 10.1038/s41467-025-66058-3

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