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

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 up

SUBMITTER: Choo JAMY 

PROVIDER: S-EPMC7366693 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature