We found that DNA nicks 5' of the (GAA)100 run led to a dramatic increase in both the rate and scale of its expansion in dividing cells. Strikingly, they also promoted large-scale expansions of carrier- and large normal-size (GAA)n repeats, recreating, in a model system, the expansion events that occur in human pedigrees. DNA nicks 3' of the (GAA)100 repeat led to a smaller but significant increase in the expansion rate as well. Our genetic analysis implies that in dividing cells, conversion of nicks into double-strand breaks (DSBs) during DNA replication followed by DSB or fork repair leads to repeat expansions. Finally, we showed that 5' GAA-strand nicks increase expansion frequency in nondividing yeast cells, albeit to a lesser extent than in dividing cells.
Tuesday, December 10, 2024
Recurrent DNA nicks drive massive expansions of (GAA)n repeats
Li L, Scott WS, Khristich AN, Armenia JF, Mirkin SM. Recurrent DNA nicks drive massive expansions of (GAA)n repeats. Proc Natl Acad Sci U S A. 2024 Dec 3;121(49):e2413298121. doi: 10.1073/pnas.2413298121. Epub 2024 Nov 25. PMID: 39585990.
