WEE1 inhibitors trigger GCN2-mediated activation of the integrated stress response.

ABSTRACT: The WEE1 kinase negatively regulates CDK1/2 to control DNA replication and mitotic entry. Genetic factors that determine sensitivity to WEE1 inhibitors (WEE1i) are largely unknown. A genome-wide insertional mutagenesis screen revealed that mutation of EIF2A, a translation regulator, sensitized to WEE1i. Additionally, a genome-wide CRISPR-Cas9 screen revealed that inactivation of integrated stress response (ISR) kinase GCN2 or its co-factor GCN1 rescued WEE1i-mediated cytotoxicity. Conversely, loss of the collided ribosome sensor ZNF598 increased sensitivity to WEE1i. Mechanistically, WEE1i induced paradoxical GCN2 activation, ATF4 upregulation, and altered ribosome dynamics. ISR activation was independent of WEE1 presence, pointing at off-target GCN2 engagement by multiple chemically disti

SUBMITTER: Tjeerdsma RB 

PROVIDER: S-EPMC12749252 | biostudies-literature | 2025 Nov

REPOSITORIES: biostudies-literature