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MutS? abundance and Msh3 ATP hydrolysis activity are important drivers of CTG•CAG repeat expansions.


ABSTRACT: CTG•CAG repeat expansions cause at least twelve inherited neurological diseases. Expansions require the presence, not the absence, of the mismatch repair protein MutS? (Msh2-Msh3 heterodimer). To evaluate properties of MutS? 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 MutS?, potentially masking the effects of biochemical alterations of the variations. Here, human Msh3 was mutated to selectively inactivate MutS?. 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 MutS? on expansions. Msh3 overexpression led to high expansion activity and elevated levels of MutS? complex, indicating that MutS? abundance drives expansions. An ATPase-defective 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 MutS? and rely heavily on Msh3 ATPase function.

SUBMITTER: Keogh N 

PROVIDER: S-EPMC5622409 | BioStudies | 2017-01-01T00:00:00Z

REPOSITORIES: biostudies

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