Chronic exposure to cadmium and antioxidants does not affect the dynamics of expanded CAG•CTG trinucleotide repeats in a mouse cell culture system of unstable DNA

Gomes-Pereira, M. and Monckton, D. G. (2021) Chronic exposure to cadmium and antioxidants does not affect the dynamics of expanded CAG•CTG trinucleotide repeats in a mouse cell culture system of unstable DNA. Frontiers in Cellular Neuroscience, 14, 606331. (doi: 10.3389/fncel.2020.606331) (PMID:33603644) (PMCID:PMC7884634)

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Abstract

More than 30 human disorders are caused by the expansion of simple sequence DNA repeats, among which triplet repeats remain the most frequent. Most trinucleotide repeat expansion disorders affect primarily the nervous system, through mechanisms of neurodysfunction and/or neurodegeneration. While trinucleotide repeat tracts are short and stably transmitted in unaffected individuals, disease-associated expansions are highly dynamic in the germline and in somatic cells, with a tendency towards further expansion. Since longer repeats are associated with increasing disease severity and earlier onset of symptoms, intergenerational repeat size gains account for the phenomenon of anticipation. In turn, higher levels of age-dependent somatic expansion have been linked with increased disease severity and earlier age of onset, implicating somatic instability in the onset and progression of disease symptoms. Hence, tackling the root cause of symptoms through the control of repeat dynamics may provide therapeutic modulation of clinical manifestations. DNA repair pathways have been firmly implicated in the molecular mechanism of repeat length mutation. The demonstration that repeat expansion depends on functional DNA mismatch repair (MMR) proteins, points to MMR as a potential therapeutic target. Similarly, a role of DNA base excision repair (BER) in repeat expansion has also been suggested, particularly during the removal of oxidative lesions. Using a well-characterized mouse cell model system of an unstable CAG•CTG trinucleotide repeat, we tested if expanded repeat tracts can be stabilized by small molecules with reported roles in both pathways: cadmium (an inhibitor of MMR activity) and a variety of antioxidants (capable of neutralizing oxidative species). We found that chronic exposure to sublethal doses of cadmium and antioxidants did not result in significant reduction of the rate of trinucleotide repeat expansion. Surprisingly, manganese yielded a significant stabilization of the triplet repeat tract. We conclude that treatment with cadmium and antioxidants, at doses that do not interfere with cell survival and cell culture dynamics, is not sufficient to modify trinucleotide repeat dynamics in cell culture.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Monckton, Professor Darren
Authors: Gomes-Pereira, M., and Monckton, D. G.
College/School:College of Medical Veterinary and Life Sciences > Institute of Molecular Cell and Systems Biology
Journal Name:Frontiers in Cellular Neuroscience
Publisher:Frontiers Media
ISSN:1662-5102
ISSN (Online):1662-5102
Published Online:02 February 2021
Copyright Holders:Copyright © 2021 Gomes-Pereira and Monckton
First Published:First published in Frontiers in Cellular Neuroscience 14:606331
Publisher Policy:Reproduced under a Creative Commons license

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
Trans-acting chemical modifiers of DNA repeat stability in vitro and in vivo - towards novel therapies in the triplet repeat expansion disordersDarren MoncktonWellcome Trust (WELLCOTR)066213/Z/01/ZInstitute of Molecular, Cell & Systems Biology