ArticleeLife2022
Targeting DNA topoisomerases or checkpoint kinases results in an overload of chaperone systems, triggering aggregation of a metastable subproteome.
Article in eLife, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers, 1 of them a synthesis that pooled it.
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Who cites it
12 citing papers in PubMed, 1 synthesis or guideline pooled it, 18 citations in OpenAlex.
- A comparative meta-analysis of membraneless organelle-associated proteins with age related proteome of C. elegans.Cell stress & chaperones · 2022Pooled it
- Tipping the PARylation scale: Dysregulation of PAR signaling in Huntington and neurodegenerative diseases.Journal of Huntington's disease · 2025Review
- Current Understanding of Protein Aggregation in Neurodegenerative Diseases.International journal of molecular sciences · 2025Review
- Senataxin deficiency disrupts proteostasis through nucleolar ncRNA-driven protein aggregation.The Journal of cell biology · 2024Article
- N-terminal tagging of RNA Polymerase II shapes transcriptomes more than C-terminal alterations.iScience · 2024Article
- Glioblastoma and its treatment are associated with extensive accelerated brain aging.Aging cell · 2024Article
- A-T neurodegeneration and DNA damage-induced transcriptional stress.DNA repair · 2024Review
- Mechanisms and pathology of protein misfolding and aggregation.Nature reviews. Molecular cell biology · 2023Review
- Mechanisms of genotoxicity and proteotoxicity induced by the metalloids arsenic and antimony.Cellular and molecular life sciences : CMLS · 2023Review
- Cancer Metabolism: The Role of ROS in DNA Damage and Induction of Apoptosis in Cancer Cells.Metabolites · 2023Review
- Article
- DNA Damage-Mediated Neurotoxicity in Parkinson's Disease.International journal of molecular sciences · 2023Review
Corrections and comments
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Authors and funding
17 authors at 2 institutions in 2 countries.
Funding
Abstract
A loss of the checkpoint kinase ataxia telangiectasia mutated (ATM) leads to impairments in the DNA damage response, and in humans causes cerebellar neurodegeneration, and an increased risk of cancer. A loss of ATM is also associated with increased protein aggregation. The relevance and characteristics of this aggregation are still incompletely understood. Moreover, it is unclear to what extent other genotoxic conditions can trigger protein aggregation as well. Here, we show that targeting ATM, but also ATR or DNA topoisomerases, results in the widespread aggregation of a metastable, disease-associated subfraction of the proteome. Aggregation-prone model substrates, including Huntingtin exon 1 containing an expanded polyglutamine repeat, aggregate faster under these conditions. This increased aggregation results from an overload of chaperone systems, which lowers the cell-intrinsic threshold for proteins to aggregate. In line with this, we find that inhibition of the HSP70 chaperone system further exacerbates the increased protein aggregation. Moreover, we identify the molecular chaperone HSPB5 as a cell-specific suppressor of it. Our findings reveal that various genotoxic conditions trigger widespread protein aggregation in a manner that is highly reminiscent of the aggregation occurring in situations of proteotoxic stress and in proteinopathies.
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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.