The integrated stress response induces R-loops and hinders replication fork progression.

Cell Death & Disease
Josephine Ann Mun Yee ChooMatthias Dobbelstein

Abstract

The integrated stress response (ISR) allows cells to rapidly shutdown most of their protein synthesis in response to protein misfolding, amino acid deficiency, or virus infection. These stresses trigger the phosphorylation of the translation initiation factor eIF2alpha, which prevents the initiation of translation. Here we show that triggering the ISR drastically reduces the progression of DNA replication forks within 1 h, thus flanking the shutdown of protein synthesis with immediate inhibition of DNA synthesis. DNA replication is restored by compounds that inhibit eIF2alpha kinases or re-activate eIF2alpha. Mechanistically, the translational shutdown blocks histone synthesis, promoting the formation of DNA:RNA hybrids (R-loops), which interfere with DNA replication. R-loops accumulate upon histone depletion. Conversely, histone overexpression or R-loop removal by RNaseH1 each restores DNA replication in the context of ISR and histone depletion. In conclusion, the ISR rapidly stalls DNA synthesis through histone deficiency and R-loop formation. We propose that this shutdown mechanism prevents potentially detrimental DNA replication in the face of cellular stresses.

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Methods Mentioned

BETA
protein folding
transfections
Protein assay
electrophoresis
fluorescence microscopy
nucleotide exchange
dot blot
dot blots
acetylation

Key Resources (RRID) Mentioned

CVCL_0042
AB_2616025
AB_2080320
AB_2230924
AB_262044
AB_2118010
AB_302613
AB_10548193
AB_2264109
AB_2651187

Software Mentioned

Plot
Graph Pad Prism
Fiji

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