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

The integrated stress response (ISR) allows cells to rapidly shut down 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 initiatio...

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Bibliographic Details
Published inbioRxiv
Main Authors Josephine Ann Mun Yee Choo, Schloesser, Denise, Manzini, Valentina, Magerhans, Anna, Dobbelstein, Matthias
Format Paper
LanguageEnglish
Published Cold Spring Harbor Cold Spring Harbor Laboratory Press 11.03.2020
Cold Spring Harbor Laboratory
Edition1.1
Subjects
Amino acids
Cancer Biology
Deoxyribonucleic acid
DNA
DNA biosynthesis
Hybrids
Phosphorylation
Protein biosynthesis
Protein deficiency
Protein folding
Protein synthesis
Proteins
R-loops
Replication forks
Ribonucleic acid
RNA
Shutdowns
Translation
GCN2
Thapsigargin
DNA replication
histones
Integrated stress response
PKR
ISRIB
PERK
eIF2alpha
R-loops
BEPP
DNA fiber assays
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Summary:The integrated stress response (ISR) allows cells to rapidly shut down 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 one hour, 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. Histone depletion alone induces R-loops and compromises DNA replication. 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.
Bibliography:SourceType-Working Papers-1
ObjectType-Working Paper/Pre-Print-1
content type line 50
ISSN:2692-8205
2692-8205
DOI:10.1101/2020.03.11.987131