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

Dörthe Gertzmann1, Cornelius Presek1, Anna Lena Mattes1

  • 1Department of Biochemistry and Cell Biology, Theodor Boveri Institute, Biocenter, Julius Maximilian University Würzburg, Am Hubland, 97074, Würzburg, Germany.

EMBO Reports
|July 4, 2025
PubMed

Insights

Oncogenic YAP causes replication stress by shortening G1 phase, leading to DNA damage. Targeting this vulnerability with CHK1 inhibitors offers a potential therapeutic strategy for YAP-dependent cancers.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Cancer Research

Background:

  • Replication stress drives genomic instability and cancer by causing DNA damage and mutations.
  • The Hippo signaling pathway's co-activator, YAP, regulates cell growth and differentiation, but its role in generating therapy-exploitable replication stress is unknown.

Purpose of the Study:

  • To investigate whether oncogenic YAP generates replication stress that can be therapeutically exploited.
  • To elucidate the mechanisms by which YAP induces replication stress and identify potential therapeutic vulnerabilities.

Main Methods:

  • Analysis of cell cycle progression and DNA replication dynamics in cells expressing oncogenic YAP.
  • Assessment of DNA damage and sensitivity to CHK1 inhibition in YAP-expressing cells.
  • Investigation of the role of YAP-TEAD interaction, transcription, and transcription-replication conflicts (TRCs) in YAP-induced replication stress.

Main Results:

  • Oncogenic YAP shortens G1 phase via CDK4/6, causing early S-phase entry, origin underlicensing, and accelerated replication fork speed.
  • CHK1 inhibition in YAP-expressing cells leads to S-phase DNA damage, dependent on YAP-TEAD interaction, global transcription increase, and heightened TRCs.
  • YAP-induced replication stress can be alleviated by restoring G1 length or reducing YAP-driven hypertranscription.

Conclusions:

  • Oncogenic YAP induces a unique form of replication stress characterized by accelerated replication fork speed and increased transcription-replication conflicts.
  • Targeting YAP-dependent cancer cells by exploiting their vulnerability to replication stress, particularly through CHK1 inhibition or modulation of transcription, presents a promising therapeutic avenue.
Keywords:
CDK4/6CHK1Replication StressYAP

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