Surtees Describes Potential Culprit in Neurodegenerative Diseases

In collaboration with researchers at the University of Rochester Medical School, Surtees and her lab have elucidated the means by which a DNA mismatch repair promotes trinucleotide repeat expansions (TNR), the genetic basis for Huntington’s disease, myotonic dystrophy and other neurodegenerative disorders.

“This is the first time that a real mechanism has been described for replication and repair factors in promoting expansions,” says Surtees, whose research was published in the Aug. 30 issue of Cell Reports.

Although genetic evidence indicates errors in DNA replication and repair cause neurodegenerative diseases, clear molecular mechanisms have not been described until now.

Surtees and colleagues studied the role of the mismatch repair complex Msh2-Msh3 in TNR expansions. The complex previously had been shown to promote expansions in mouse models of Huntington’s disease and myotonic dystrophy, but researchers did known how this happened.

The current research indicates that Msh2-Msh3 interferes with normal DNA processing at the replication fork, particularly in the presence of trinucleotide repeats, leading to incremental increases in repeat lengths during processing.

This mismatch repair system, best known for its role in post-replicative mismatch repair, provides a critical line of defense in protecting the integrity of the genome. Researchers don’t fully understand the molecular mechanisms for these critical repair pathways, which regulate genome stability. Surtees aims to learn how the correct repair pathway is initiated.

In the long term, she seeks to examine and clarify the mechanisms that bridge damage recognition by MSH complexes and DNA repair.