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MLH3, a minor player in mismatch repair, is a major force in GAA•TTC repeat expansion (736.9)
Author(s) -
Fuselier Kayla,
Grabczyk Ed
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.736.9
Subject(s) - frataxin , trinucleotide repeat expansion , ataxia , biology , dna mismatch repair , genetics , microbiology and biotechnology , gene , dna repair , neuroscience , allele , iron binding proteins
Friedreich ataxia (FRDA) is a progressive neurodegenerative disorder caused by GAA·TTC repeat expansion in the first intron of the frataxin (FXN) gene. Disease severity correlates with the length of the expanded repeats and the reduction of FXN mRNA. Our objective is to refine our understanding of the role mismatch repair proteins play in the repeat expansion that causes FRDA. We have previously shown that the expansion rate is associated with transcription within the repeat and requires MutSβ and the subsequent action of a MutL complex. We now demonstrate that the necessary complex is MutLγ, a heterodimer of MLH1 and MLH3. We report here that our studies on MLH3 indicate that it is pivotal in GAA•TTC expansion in our human cell model system. MLH1 has a central role in all MutL complexes; whereas MLH3 is only a component of the MutLγ complex. Therefore, MLH3 may be the better potential therapeutic target for FRDA. Grant Funding Source : Supported by the Friedreich's Ataxia Research Alliance and the LSUHSC Research Enhancement Fund