Genome alterations arise from inaccurate DNA repair, accumulating into distinct mutational signatures. Here, we investigate the role of every genomically encoded gene in double-strand break (DSB) repa...

Perturbed DNA replication can lead to incompletely replicated DNA when cells enter mitosis and can interfere with chromosome segregation. Cells therefore require mechanisms to resolve these lesions du...

How cells ensure that they enter mitosis after completing replication of their genome is not fully resolved. Sobkowiak et al. describe a checkpoint involving REV7. This checkpoint has mechanistic similarities to the spindle anaphase checkpoint mediated by…

Here the authors reveal how telomeres signal mitotic stress. A key protein network alters their structure exposing telomere ends to signal mitotic stress, ultimately triggering a controlled DNA damage...

Inhibitors of the protein kinase WEE1 have emerged as promising agents for cancer therapy. In this study, we uncover synergistic interactions between WEE1 small-molecule inhibitors and defects in mRNA translation, mediated by activation of the integrated stress response (ISR) through the kinase GCN2. Using a pooled CRISPRi screen, we identify GSPT1 and ALKBH8 as factors whose depletion confer hypersensitivity to the WEE1 inhibitor, AZD1775. We demonstrate that this synergy depends on ISR activation, which is induced by the off-target activity of WEE1 inhibitors. Furthermore, PROTAC-based WEE1 inhibitors and molecular glues show reduced or no ISR activation, suggesting potential strategies to minimise off-target toxicity. Our findings reveal that certain WEE1 inhibitors elicit dual toxicity via ISR activation and genotoxic stress, with ISR activation being independent of WEE1 itself or cell-cycle status. This dual mechanism highlights opportunities for combination therapies, such as pairing WEE1 inhibitors with agents targeting the mRNA translation machinery. This study also underscores the need for more precise WEE1 targeting strategies to mitigate off-target effects, with implications for optimising the therapeutic potential of WEE1 inhibitors. ### Competing Interest Statement The authors have declared no competing interest.

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 inser...

Tumor cells upregulate compensatory buffering genes following tumor suppressor loss. These genes may represent new synthetic lethal partners that could be harnessed therapeutically.

Schmid and Walter train a classifier that discerns functionally relevant structure predictions in proteome-wide protein-protein interaction (PPI) screens using AlphaFold-Multimer, and they use this co...

The University of Cologne is one of the oldest and largest universities in Germany. With its six Faculties covering a broad spectrum of disciplines and its i...

DNA replication is essential to life and ensures the accurate transmission of genetic information, which is significantly disturbed during cancer development and chemotherapy. While DNA replication is...

Extrachromosomal DNA (ecDNA) are circular DNA bodies that play critical roles in tumor progression and treatment resistance by amplifying oncogenes across a wide range of cancer types. ecDNA lack cent...

The Center for Epigenetic Cell Memory (EpiC) is a new Center of Excellence that will be established based on funding by the Danish National Research Foundation.