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The Ubiquitin Ligase TRIP12 Limits PARP1 Trapping and Constrains PARP Inhibitor Efficiency

Marco Gatti1, Ralph Imhof1, Qingyao Huang2

  • 1Department of Molecular Mechanisms of Disease, University of Zurich, Zurich 8057, Switzerland.

Cell Reports
|August 7, 2020
PubMed

Insights

The ubiquitin E3 ligase TRIP12 regulates sensitivity to PARP inhibitors (PARPi) by controlling PARP1 protein levels. Loss of TRIP12 increases PARP1 trapping, leading to cancer cell death.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • PARP inhibitors (PARPi) exploit synthetic lethality in BRCA-deficient tumors.
  • Understanding PARPi vulnerabilities beyond BRCA mutations and homologous recombination repair (HDR) defects is crucial.

Purpose of the Study:

  • To identify novel regulators of PARPi sensitivity.
  • To investigate the role of the ubiquitin E3 ligase TRIP12 in PARPi response.

Main Methods:

  • Assessed TRIP12's regulation of PARP1 levels and PARPi-induced PARP1 trapping.
  • Investigated TRIP12's mechanism of PARP1 ubiquitylation and degradation.
  • Correlated TRIP12 expression with PARP1 abundance in patient cohorts.

Main Results:

  • TRIP12 negatively regulates PARPi sensitivity by controlling steady-state PARP1 levels.
  • TRIP12 limits cytotoxic PARP1 trapping induced by PARPi.
  • TRIP12 polyubiquitylates PARP1, targeting it for proteasomal degradation.
  • Loss of TRIP12 leads to increased DNA replication stress, damage, cell cycle arrest, and cell death.
  • PARP1 abundance inversely correlates with TRIP12 expression in breast and ovarian cancers.

Conclusions:

  • TRIP12 is a key regulator of PARP1 stability and PARPi-induced trapping.
  • TRIP12 modulation has implications for PARPi sensitivity and resistance in cancer therapy.
Keywords:
BRCA mutationsHECT-type ubiquitin ligasesPAR-targeted protein ubiquitylationPARP inhibitorscancerendogenous DNA lesionsgenome instabilitypersonalized cancer therapyreplication stresssynthetic lethality

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