DNA Repair Protein Could Be Key to Understanding FA Progression, Study Suggests

DNA Repair Protein Could Be Key to Understanding FA Progression, Study Suggests
This post was originally published on this site

MLH3 GAA repeats

Using human cells, researchers have found that targeting the MLH3 protein involved in DNA repair can reduce the GAA repeat expansion that causes Friedreich’s ataxia.

This finding adds new knowledge about the mechanisms involved in Friedreich’s ataxia, but it also may lead to new development of disease-modifying therapies.

The finding was reported in the study titled, “GAA•TTC repeat expansion in human cells is mediated by mismatch repair complex MutLγ and depends upon the endonuclease domain in MLH3 isoform one,” published in Nucleic Acids Research.

Cells have several mechanisms to ensure that their genetic code is correct. However, these systems can fail, promoting the increase of potential disease-causing mutations. One of these systems is DNA mismatch repair (MMR), which comprises the MutS complex that recognizes genetic errors and the MutL protein that promotes their repair.

In the case of repetitive sequences, the MMR system has been found to actually contribute to genetic instability. The MutS complex has been implicated in the promotion of GAA expansions that cause Friedreich’s ataxia, along with other code expansions that cause other diseases such as Huntington’s disease and myotonic dystrophy.

A team led by Anasheh Halabi, MD, PhD, from the University of California, San Diego, evaluated the contribution of MutL complex in promoting GAA expansions in Friedreich’s ataxia. MutL complexes combine the MLH1 protein, the core subunit of the complex, with one of three partners — PMS2, PMS1, or MLH3.

To evaluate its role, the team genetically manipulated human cells to silence the genes encoding MutL proteins. The cells carried 176 repetitions of the GAA sequence, similar to what is found in patients with Friedreich’s ataxia.

They found that cells that lack MLH1 had significantly reduced expansion of GAA repeats compared to control cells. This reduction was also reported in cells that lacked MLH3, but not PMS2. These findings strongly suggest that the MLH1-MLH3 complex may be implicated in GAA triplet expansion, and therefore, disease development.

Next, the team tested the potential of the splice-switching oligonucleotide (SSO) strategy to prevent MLH3 production. This involves small molecules that bind to RNA sequences and promote skipping of small coding regions.

SSO is being explored as a therapeutic strategy to treat genetic disorders, such as Duchenne muscular dystrophy. In addition, one SSO-based therapy was recently approved by the U.S. Food and Drug Administration for the treatment of spinal muscular atrophy.

With SSO, the team expected to produce a smaller MLH3 protein that, while still resembling the original version, would not be functional and partake in the MLH1-MLH3 complex.

They treated cells with SSO to achieve constant production of smaller MLH3 protein. After four weeks of treatment, the cells showed slower GAA repeat expansion, similar to that seen in the previous experiment. The inhibitory effect was found to be dependent on the amount of SSO used.

Next, they tested SSO strategy in cells collected from three patients with Friedreich’s ataxia. After six weeks of treatment, the cells showed reduced levels of functional MLH3 protein and slower GAA expansion rate. Still, the results were variable between the different samples, which could be explained in part by the individual variability of the patients.

Collectively, these results demonstrate that the MLH1-MLH3 complex is an important mediator of GAA expansion. Additionally, targeting MLH3 promoters may hold potential for treating Friedreich’s ataxia.

“SSO mediated skipping of MLH3 may provide a basis for the development of novel therapeutic agents,” the researchers stated. “Particularly as more data suggests that MLH3 is part of a central mechanism shared by repeat expansion disorders.”

The post DNA Repair Protein Could Be Key to Understanding FA Progression, Study Suggests appeared first on Friedreich’s Ataxia News.

Chris Comish serves as the Publisher of the website, and is responsible for directing the editorial focus as well as putting the finishing touches on many featured articles.