158: Interruptions in repeat expansion diseases and the SD-MMEJ hypothesis

Aston AN et al., Trends in Genetics - This opinion article reviews how short sequence interruptions within expanded tandem repeats alter somatic instability and clinical outcomes across multiple repeat expansion diseases, and proposes synthesis-dependent microhomology-mediated end joining (SD-MMEJ) as a unifying mechanism to explain the gain, loss, and complexity of interruptions. Key terms: repeat expansion, interruptions, SD-MMEJ, DNA repair, Huntington's disease.

Study Highlights:
Interruptions within expanded tandem repeats modulate somatic expansion and clinical severity and are observed to be dynamic, recurrent, locus-specific, and enriched near repeat–flank boundaries. The authors synthesize literature and sequencing observations to show interruptions can arise or be lost within a single generation and can form highly complex alleles. They propose SD-MMEJ, a Polθ-dependent alternative end-joining pathway, as a mechanism that produces insertions, deletions and repeating patterns via priming, synthesis and microhomology annealing after double-strand breaks. The model makes testable predictions about the role of flanking sequence structure, the need for double-strand breaks, and implications for diagnostics and therapeutic manipulation of interruptions.

Conclusion:
SD-MMEJ is presented as a plausible, testable mechanism that can account for most documented interruption dynamics; validating this model could improve interpretation of long-read sequencing, illuminate links between repair pathways and repeat instability, and suggest routes for therapeutic intervention.

Music:
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Article title:
Interruptions impact clinical features of repeat expansion diseases, but how are they gained and lost?

First author:
Aston AN

Journal:
Trends in Genetics

DOI:
10.1016/j.tig.2025.07.005

Reference:
Aston AN, Dion V. Interruptions impact clinical features of repeat expansion diseases, but how are they gained and lost? Trends in Genetics (2025). https://doi.org/10.1016/j.tig.2025.07.005

License:
This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/

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