Cas9 nickase-mediated contractions of CAG/CTG repeats are transcription-dependent and replication-independent

Larin, Meghan, Gidney, Florence, Aeschbach, Lorene, Heraty, Laura, Randall, Emma, Heuchan, Aeverie, Buncova, Marcela, Berard, Melvin and Dion, Vincent ORCID: https://orcid.org/0000-0003-4953-7637 2024. Cas9 nickase-mediated contractions of CAG/CTG repeats are transcription-dependent and replication-independent. NAR Molecular Medicine 1 (4) , ugae013. 10.1093/narmme/ugae013

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Abstract

There is currently no disease-modifying treatment for expanded CAG/CTG repeat disorders. Given that longer repeat tracts lead to an earlier age of disease onset and faster progression, contracting them is expected to improve symptoms and/or delay onset. We have previously demonstrated that the Cas9 D10A nickase can effectively contract CAG/CTG repeats when targeted to the repeat tract itself. However, the mechanism remains unclear. Here, we tested whether nickase-mediated contractions depend on transcription or on replication using human cell models. We find that transcription promotes contractions and that they occur independently of the rate of cell division. These results support the therapeutic potential of this approach in non-dividing cells.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Publisher:	Oxford University Press
ISSN:	2976-856X
Date of First Compliant Deposit:	17 September 2024
Date of Acceptance:	21 September 2024
Last Modified:	24 Oct 2024 10:30
URI:	https://orca.cardiff.ac.uk/id/eprint/172170

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