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Ku70 Binding to YAP Alters PARP1 Ubiquitination to Regulate Genome Stability and Tumorigenesis

Yinyin Shu1, Xiaoni Jin1, Mintao Ji1

  • 1State Key Laboratory of Radiation Medicine and Protection, Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Jiangsu Key Laboratory of Infection and Immunity, The Fourth Affiliated Hospital of Soochow University, School of Radiation Medicine and Protection, Suzhou Medical College of Soochow University, Suzhou, China.

Cancer Research
|June 11, 2024
PubMed

Insights

Loss of Ku70 protein enhances Yes-associated protein (YAP) activity, leading to PARP1 degradation and increased genome instability. This promotes cancer development in colon and liver cancers.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Genetics

Background:

  • Yes-associated protein (YAP) is crucial in cancer, with emerging roles in DNA damage response.
  • The interplay between YAP/TAZ and DNA repair pathways is not fully understood.

Purpose of the Study:

  • To elucidate the mechanisms connecting DNA damage repair and YAP activity.
  • To investigate the role of Ku70 in regulating YAP's transcriptional function and its impact on tumorigenesis.

Main Methods:

  • Investigated the interaction between Ku70, YAP, and TEAD4 using biochemical assays.
  • Assessed YAP transcriptional activity upon Ku70 depletion.
  • Utilized in vivo models of colon cancer and hepatocellular carcinoma (HCC).
  • Examined the effect of YAP on DNA damage repair via the SMURF2-mediated ubiquitin-proteasome pathway.
  • Analyzed patient HCC samples for correlations between Ku70, YAP, PARP1, and genome instability.

Main Results:

  • Ku70 competes with TEAD4 for YAP binding, thus limiting YAP's transcriptional activity.
  • Ku70 depletion increases YAP-TEAD4 interaction, boosting YAP activity and enhancing tumorigenesis in vivo.
  • YAP promotes genome instability by inducing PARP1 degradation through SMURF2, thereby impairing DNA damage repair.
  • HCC patient data confirm a link between low Ku70, high YAP activity, low PARP1, and increased genome instability.

Conclusions:

  • A novel Ku70-YAP-PARP1 axis regulates genome stability.
  • Disruption of this axis, particularly through Ku70 loss, drives tumorigenesis by increasing YAP activity and DNA damage.
  • Targeting this pathway could offer new therapeutic strategies for YAP-driven cancers.

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