Oncogenic YAP sensitizes cells to CHK1 inhibition via CDK4/6 driven G1 acceleration

ABSTRACT: Replication stress is a driver of genomic instability, contributing to carcinogenesis by causing DNA damage and mutations. While YAP, the downstream co-activator of the Hippo signaling pathway, plays a crucial role in regulating cell growth and differentiation, it is unclear whether it generates replication stress exploitable for therapy. Here, we report that oncogenic YAP shortens the G1 phase through increased CDK4/6 activity, leading to early S-phase entry. This causes origin under-licensing, an overall reduced rate of DNA replication, and, untypically, an accelerated speed of individual replication forks. CHK1 inhibition in cells expressing oncogenic YAP results in DNA damage during S-phase, which is not due to premature CDK1 activation or mitotic entry. Sensitivity to CHK1 inhibition

SUBMITTER: Dörthe Gertzmann 

PROVIDER: S-SCDT-10_1038-S44319-025-00514-5 | biostudies-other |

REPOSITORIES: biostudies-other