MutSß abundance and Msh3 ATP hydrolysis activity are important drivers of CTG•CAG repeat expansions

Norma Keogh, Kara Y. Chan, Guo Min Li, Robert S. Lahue

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

CTG•CAG repeat expansions cause at least twelve inherited neurological diseases. Expansions require the presence, not the absence, of the mismatch repair protein MutSß (Msh2-Msh3 heterodimer). To evaluate properties of MutSß that drive expansions, previous studies have tested under-expression, ATPase function or polymorphic variants of Msh2 and Msh3, but in disparate experimental systems. Additionally, some variants destabilize MutSß, potentially masking the effects of biochemical alterations of the variations. Here, human Msh3 was mutated to selectively inactivate MutSß. Msh3-/- cells are severely defective for CTG•CAG repeat expansions but show full activity on contractions. Msh3-/- cells provide a single, isogenic system to add back Msh3 and test key biochemical features of MutSß on expansions. Msh3 overexpression led to high expansion activity and elevated levels of MutSß complex, indicating that MutSß abundance drives expansions. An ATPasedefective Msh3 expressed at normal levels was as defective in expansions as Msh3-/- cells, indicating that Msh3 ATPase function is critical for expansions. Expression of two Msh3 polymorphic variants at normal levels showed no detectable change in expansions, suggesting these polymorphisms primarily affect Msh3 protein stability, not activity. In summary, CTG•CAG expansions are limited by the abundance of MutSß and rely heavily on Msh3 ATPase function.

Original languageEnglish (US)
Pages (from-to)10068-10078
Number of pages11
JournalNucleic Acids Research
Volume45
Issue number17
DOIs
StatePublished - Sep 1 2017

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Adenosine Triphosphatases
Hydrolysis
Adenosine Triphosphate
DNA Mismatch Repair
Protein Stability
Proteins

ASJC Scopus subject areas

  • Genetics

Cite this

MutSß abundance and Msh3 ATP hydrolysis activity are important drivers of CTG•CAG repeat expansions. / Keogh, Norma; Chan, Kara Y.; Li, Guo Min; Lahue, Robert S.

In: Nucleic Acids Research, Vol. 45, No. 17, 01.09.2017, p. 10068-10078.

Research output: Contribution to journalArticle

Keogh, Norma ; Chan, Kara Y. ; Li, Guo Min ; Lahue, Robert S. / MutSß abundance and Msh3 ATP hydrolysis activity are important drivers of CTG•CAG repeat expansions. In: Nucleic Acids Research. 2017 ; Vol. 45, No. 17. pp. 10068-10078.
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