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Updated: Aug 5, 2026

Electrophoretic Analysis of Replication Through Structure-Prone DNA Repeats Within the SV40-Based Human Episome
05:22

Electrophoretic Analysis of Replication Through Structure-Prone DNA Repeats Within the SV40-Based Human Episome

Published on: September 13, 2024

Reconciling the effects of PMS2 in different repeat expansion disease models supports a common expansion mechanism

Carson J Miller1, Diego Antonio Jimenez1, Alexandra Walker1

  • 1Section on Gene Structure and Disease, Laboratory of Cell and Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.

PNAS Nexus
|July 28, 2026
PubMed

Insights

The MutLα mismatch repair protein PMS2 impacts repeat expansion diseases (REDs) differently depending on its levels and the specific repeat. Understanding this mechanism could lead to treatments for multiple incurable REDs.

Area of Science:

  • Genetics
  • Molecular Biology
  • Genomic Instability

Background:

  • Over 45 repeat expansion diseases (REDs) are caused by expanded tandem repeats.
  • Most REDs are incurable, highlighting the need for effective therapeutic strategies.
  • The role of PMS2 in repeat expansion is contradictory across different models, suggesting complex mechanisms.

Purpose of the Study:

  • To investigate the shared mechanisms underlying repeat expansion in REDs.
  • To determine the role of PMS2 in repeat expansion across different RED models.
  • To explore how PMS2 levels influence repeat expansion and its potential therapeutic implications.

Main Methods:

  • Utilized mouse models for two distinct REDs.
  • Analyzed the effects of PMS2 loss on repeat expansion in various tissues.
  • Investigated PMS2's role in mouse embryonic stem cells, manipulating PMS2 levels.
  • Assessed the dependence of expansion promotion on the PMS2 nuclease domain.

Main Results:

  • PMS2 exhibited varied effects, increasing expansion in some tissues and decreasing it in others across two RED models.
  • Lower PMS2 levels promoted repeat expansion, while higher levels conferred protection in mouse embryonic stem cells.
  • The nuclease activity of PMS2 was crucial for its role in promoting expansion.

Conclusions:

  • Findings support a common expansion mechanism across different REDs.
  • PMS2 plays a dual role in repeat expansion, influenced by its concentration and nuclease activity.
  • This research provides critical insights into RED pathogenesis and potential therapeutic targets.
Keywords:
Huntington's diseaseMutLαMutLβMutLγfragile X–related disorders

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