Targeting DNA topoisomerases or checkpoint kinases results in an overload of chaperone systems, triggering aggregation of a metastable subproteome

Wouter Huiting, Suzanne L Dekker, Joris C J van der Lienden, Rafaella Mergener, Maiara K Musskopf, Gabriel V Furtado, Emma Gerrits, David Coit, Mehrnoosh Oghbaie, Luciano H Di Stefano, Hein Schepers, Maria A W H van Waarde-Verhagen, Suzanne Couzijn, Lara Barazzuol, John LaCava, Harm H Kampinga, Steven Bergink*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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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.

Original languageEnglish
Article numbere70726
Number of pages29
JournaleLife
Volume11
DOIs
Publication statusPublished - 24-Feb-2022

Keywords

  • genotoxic stress
  • protein homeostasis
  • protein aggregation
  • DNA damage response
  • chaperone
  • Human
  • HEAT-SHOCK PROTEINS
  • ALPHA-B-CRYSTALLIN
  • MOLECULAR CHAPERONE
  • NEURODEGENERATIVE DISEASES
  • POLYGLUTAMINE AGGREGATION
  • PHASE-TRANSITION
  • STRESS-PROTEIN
  • ATM
  • PROTEOSTASIS
  • ALZHEIMERS

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