MutLγ promotes repeat expansion in a Fragile X mouse model while EXO1 is protective

The Fragile X-related disorders (FXDs) are Repeat Expansion Diseases resulting from an expansion of a CGG-repeat tract at the 5' end of the FMR1 gene. The mechanism responsible for this unusual mutation is not fully understood. We have previously shown that mismatch repair (MMR) complexes, MSH2...

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Published in:PLoS genetics 2018-10, Vol.14 (10), p.e1007719-e1007719
Main Authors: Zhao, Xiaonan, Zhang, Yongwei, Wilkins, Kenneth, Edelmann, Winfried, Usdin, Karen
Format: Article
Language:English
Subjects:
Base excision repair
Biology and Life Sciences
Deoxyribonucleic acid
Diabetes
DNA
DNA repair
DNA-directed DNA polymerase
Exonuclease
FMR1 protein
Genetic factors
Huntingtons disease
Intellectual disabilities
Kidney diseases
Laboratories
Medicine and Health Sciences
Mismatch repair
MLH1 protein
Molecular biology
MSH2 protein
MSH6 protein
Mutation
Nuclease
Point mutation
Proteins
Research and Analysis Methods
Yeast
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Summary:The Fragile X-related disorders (FXDs) are Repeat Expansion Diseases resulting from an expansion of a CGG-repeat tract at the 5' end of the FMR1 gene. The mechanism responsible for this unusual mutation is not fully understood. We have previously shown that mismatch repair (MMR) complexes, MSH2/MSH3 (MutSβ) and MSH2/MSH6 (MutSα), together with Polβ, a DNA polymerase important for base excision repair (BER), are important for expansions in a mouse model of these disorders. Here we show that MLH1/MLH3 (MutLγ), a protein complex that can act downstream of MutSβ in MMR, is also required for all germ line and somatic expansions. However, exonuclease I (EXO1), which acts downstream of MutL proteins in MMR, is not required. In fact, a null mutation in Exo1 results in more extensive germ line and somatic expansions than is seen in Exo1+/+ animals. Furthermore, mice homozygous for a point mutation (D173A) in Exo1 that eliminates its nuclease activity but retains its native conformation, shows a level of expansion that is intermediate between Exo1+/+ and Exo1-/- animals. Thus, our data suggests that expansion of the FX repeat in this mouse model occurs via a MutLγ-dependent, EXO1-independent pathway, with EXO1 protecting against expansion both in a nuclease-dependent and a nuclease-independent manner. Our data thus have implications for the expansion mechanism and add to our understanding of the genetic factors that may be modifiers of expansion risk in humans.
ISSN:1553-7404
1553-7390
1553-7404
DOI:10.1371/journal.pgen.1007719