Department of Biomedical Sciences of Cells and Systems, University Medical Center Groningen, University of Groningen, Groningen, Netherlands
Maiara K Musskopf
Department of Biomedical Sciences of Cells and Systems, University Medical Center Groningen, University of Groningen, Groningen, Netherlands
Gabriel V Furtado
Department of Biomedical Sciences of Cells and Systems, University Medical Center Groningen, University of Groningen, Groningen, Netherlands
Emma Gerrits
Department of Biomedical Sciences of Cells and Systems, University Medical Center Groningen, University of Groningen, Groningen, Netherlands
David Coit
Laboratory of Cellular and Structural Biology, The Rockefeller University, New York, United States
Mehrnoosh Oghbaie
Laboratory of Cellular and Structural Biology, The Rockefeller University, New York, United States; European Research Institute for the Biology of Ageing, University Medical Center Groningen, University of Groningen, Groningen, Netherlands
Luciano H Di Stefano
European Research Institute for the Biology of Ageing, University Medical Center Groningen, University of Groningen, Groningen, Netherlands
Department of Biomedical Sciences of Cells and Systems, University Medical Center Groningen, University of Groningen, Groningen, Netherlands; Department of Radiation Oncology, University Medical Center Groningen, University of Groningen, Groningen, Netherlands
Laboratory of Cellular and Structural Biology, The Rockefeller University, New York, United States; European Research Institute for the Biology of Ageing, University Medical Center Groningen, University of Groningen, Groningen, Netherlands
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.
