Document Type

Article

Publication Date

11-26-2025

Comments

This article is the author’s final published version in Nucleic Acids Research, Volume 53, Issue 22, 2025, Article number gkaf1393.

The published version is available at https://doi.org/10.1093/nar/gkaf1393. Copyright © The Author(s) 2025.

 See Correction in Additional Files section below.

Abstract

DNA triplet repeat expansion causes several primarly neurological disorders like Huntington's disease, myotonic dystrophy type 1, and fragile-X related disorders. There is general consensus that recognition of extrahelical extrusions or hairpin-loop structures (formed by strand slippage) by the DNA mismatch repair protein MutSβ leads to repeat expansion by a mutagenic process. By contrast, the FAN1 nuclease attenuates triplet repeat expansion, the molecular basis of which was explained by our recent finding that FAN1 nuclease cleaves and initiates removal of extrahelical extrusions. Here we show that extrusions containing two or more triplet repeats are subject to recognition and processing by either FAN1 or MutSβ. However, extrusions containing a single triplet escape FAN1 cleavage and are preferentially processed by a MutSβ-dependent process, leading to repeat expansion. Thus, extrahelical extrusion size determines the ultimate fate of the repeat element, the protective role of FAN1 being limited to removal of extrusions containing two or more triplets. Therefore, repeat expansion is a net consequence of MutSβ-dependent processing of single triplet extrusions and competition between MutSβ and FAN1 for extrusions containing two or more triplets. These findings provide new insights into the role of DNA structural dynamics in determining pathway choice in DNA repair.

Creative Commons License

Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.

Additional Files
Supplementary Materials.zip (685 kB)
Correction.pdf (112 kB)

PubMed ID

41428735

Language

English

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