ArticleProceedings of the National Academy of Sciences of the United States of America2013
Proteasome inhibition rescues clinically significant unstable variants of the mismatch repair protein Msh2.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
25 citing papers in PubMed, 50 citations in OpenAlex.
- Hereditary diffuse gastric cancer in progress: Comparative lessons from Lynch syndrome.European journal of human genetics : EJHG · 2026Review
- Proteasomal control of transcription factors: mechanisms, regulation and dysregulation.Cellular and molecular life sciences : CMLS · 2026Review
- PRKN-linked familial Parkinson's disease: cellular and molecular mechanisms of disease-linked variants.Cellular and molecular life sciences : CMLS · 2024Review
- Deep mutational scanning reveals a correlation between degradation and toxicity of thousands of aspartoacylase variants.Nature communications · 2024Article
- A mutational atlas for Parkin proteostasis.Nature communications · 2024Article
- Lynch syndrome, molecular mechanisms and variant classification.British journal of cancer · 2023Review
- Article
- Understanding the Origins of Loss of Protein Function by Analyzing the Effects of Thousands of Variants on Activity and Abundance.Molecular biology and evolution · 2021Article
- Multiplexing mutation rate assessment: determining pathogenicity of Msh2 variants in Saccharomyces cerevisiae.Genetics · 2021Article
- MutSα mismatch repair protein stability is governed by subunit interaction, acetylation, and ubiquitination.G3 (Bethesda, Md.) · 2021Article
- Multiplexed assays reveal effects of missense variants in MSH2 and cancer predisposition.PLoS genetics · 2021Article
- Mapping the degradation pathway of a disease-linked aspartoacylase variant.PLoS genetics · 2021Article
- Loss-of-Function Piezo1 Mutations Display Altered Stability Driven by Ubiquitination and Proteasomal Degradation.Frontiers in pharmacology · 2021Article
- Co-Chaperones in Targeting and Delivery of Misfolded Proteins to the 26S Proteasome.Biomolecules · 2020Review
- Systematic analysis of alterations in the ubiquitin proteolysis system reveals its contribution to driver mutations in cancer.Nature cancer · 2020Article
- Article
- Biophysical and Mechanistic Models for Disease-Causing Protein Variants.Trends in biochemical sciences · 2019Review
- The exocyst subunit Sec3 is regulated by a protein quality control pathway.The Journal of biological chemistry · 2017Article
- Predicting the impact of Lynch syndrome-causing missense mutations from structural calculations.PLoS genetics · 2017Article
- HuCOP1 contributes to the regulation of DNA repair in keratinocytes.Molecular and cellular biochemistry · 2017Article
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
MSH2 is required for DNA mismatch repair recognition in eukaryotes. Deleterious mutations in human MSH2 account for approximately half of the alleles associated with a common hereditary cancer syndrome. Previously, we characterized clinically identified MSH2 missense mutations, using yeast as a model system, and found that the most common cause of defective DNA mismatch repair was low levels of the variant Msh2 proteins. Here, we show that increased protein turnover is responsible for the reduced cellular levels. Increasing gene dosage of more than half of the missense alleles fully restored function. A titration experiment revealed that raising the expression level of one variant to less than wild-type levels restored mismatch repair, suggesting that overexpression is not always required to regain function. We found that the ubiquitin-mediated proteasome degradation pathway is the major mechanism for increased turnover of the Msh2 variants and identified the primary ubiquitin ligase as San1. Deletion of San1 restored protein levels for all but one variant, but did not elevate wild-type Msh2 levels. The unstable variants interacted with San1, whereas wild-type Msh2 did not. Additionally, san1Δ suppressed the mismatch repair defect of unstable variants. Of medical significance, the clinically approved drug Bortezomib partially restored protein levels and mismatch repair function for low-level variants and reversed the resistance to cisplatin, a common chemotherapeutic. Our results provide the foundation for an innovative therapeutic regime for certain mismatch-repair-defective cancers that are refractory to conventional chemotherapies.
Indexed as
Identifiers
What OpenQuestion holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.