MutSα mismatch repair protein stability is governed by subunit interaction, acetylation, and ubiquitination
| Autor: | Tim Arlow, Junwon Kim, Emma Zorensky, Mark D. Rose, Cristina Balbás Martínez, Joanna E Haye-Bertolozzi, Caitlin Fay, Alison E. Gammie |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
AcademicSubjects/SCI01140
congenital hereditary and neonatal diseases and abnormalities Saccharomyces cerevisiae Proteins DNA Repair AcademicSubjects/SCI00010 Saccharomyces cerevisiae MutS QH426-470 AcademicSubjects/SCI01180 DNA Mismatch Repair 03 medical and health sciences 0302 clinical medicine Genetics Molecular Biology neoplasms Genetics (clinical) 030304 developmental biology chemistry.chemical_classification Investigation 0303 health sciences DNA ligase biology Protein Stability Mutagenesis dimer stabilization Ubiquitination nutritional and metabolic diseases Acetylation Mismatch Repair Protein biology.organism_classification digestive system diseases Cell biology mismatch repair MutS Homolog 2 Protein MSH3 chemistry MSH2 030220 oncology & carcinogenesis AcademicSubjects/SCI00960 DNA mismatch repair |
| Zdroj: | G3: Genes|Genomes|Genetics G3: Genes, Genomes, Genetics, Vol 11, Iss 3 (2021) |
| ISSN: | 2160-1836 |
| Popis: | In eukaryotes, DNA mismatch recognition is accomplished by the highly conserved MutSα (Msh2/Msh6) and MutSβ (Msh2/Msh3) complexes. Previously, in the yeast Saccharomyces cerevisiae, we determined that deleting MSH6 caused wild-type Msh2 levels to drop by ∼50%. In this work, we determined that Msh6 steady-state levels are coupled to increasing or decreasing levels of Msh2. Although Msh6 and Msh2 are reciprocally regulated, Msh3 and Msh2 are not. Msh2 missense variants that are able to interact with Msh6 were destabilized when Msh6 was deleted; in contrast, variants that fail to dimerize were not further destabilized in cells lacking Msh6. In the absence of Msh6, Msh2 is turned over at a faster rate and degradation is mediated by the ubiquitin-proteasome pathway. Mutagenesis of certain conserved lysines near the dimer interface restored the levels of Msh2 in the absence of Msh6, further supporting a dimer stabilization mechanism. We identified two alternative forms of regulation both with the potential to act via lysine residues, including acetylation by Gcn5 and ubiquitination by the Not4 ligase. In the absence of Gcn5, Msh2 levels were significantly decreased; in contrast, deleting Not4 stabilized Msh2 and Msh2 missense variants with partial function. The stabilizing effect on Msh2 by either the presence of Msh6 or the absence of Not4 are dependent on Gcn5. Taken together, the results suggest that the wild-type MutSα mismatch repair protein stability is governed by subunit interaction, acetylation, and ubiquitination. |
| Databáze: | OpenAIRE |
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