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EZH2 promotes degradation of stalled replication forks by recruiting MUS81 through histone H3 trimethylation

Beatrice Rondinelli1,2, Ewa Gogola3, Hatice Yücel1

  • 1Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02215, USA.

Nature Cell Biology
|October 17, 2017
PubMed

Insights

EZH2 stabilizes stalled DNA replication forks by recruiting MUS81 nuclease, a key mechanism in BRCA1/2-deficient cancers. Loss of EZH2 or MUS81 promotes resistance to PARP inhibitors (PARPi) and predicts poor patient outcomes.

Area of Science:

  • * Molecular biology
  • * Cancer research
  • * Genomics

Background:

  • * Poly-ADP-ribose polymerase inhibitors (PARPi) resistance is a major challenge in treating BRCA1 and BRCA2 (BRCA1/2)-deficient tumors.
  • * Stabilization of stalled DNA replication forks is an emerging mechanism of PARPi resistance, promoting genomic stability in these cancers.
  • * Understanding the molecular pathways governing genomic stability at stalled forks is crucial.

Purpose of the Study:

  • * To investigate the role of EZH2 in regulating genomic stability at stalled DNA replication forks.
  • * To determine the molecular mechanisms by which EZH2 influences PARPi resistance in BRCA1/2-deficient cancers.
  • * To evaluate EZH2 and MUS81 as potential biomarkers for treatment response.

Main Methods:

  • * Investigated EZH2 localization at stalled replication forks.
  • * Analyzed the impact of EZH2 on histone H3 lysine 27 trimethylation (H3K27me3) and MUS81 nuclease recruitment.
  • * Assessed the consequences of EZH2/MUS81 axis dysfunction on PARPi resistance in BRCA2-deficient cells and a murine model.
  • * Correlated EZH2 and MUS81 expression levels with clinical outcomes in patients with BRCA2-mutated tumors.

Main Results:

  • * EZH2 was found to localize at stalled replication forks and mediate the recruitment of the MUS81 nuclease via H3K27me3.
  • * Reduced EZH2 levels led to decreased H3K27 methylation, impaired MUS81 recruitment, and subsequent fork stabilization.
  • * Loss of the EZH2/MUS81 axis conferred PARPi resistance in BRCA2-deficient cells.
  • * Low EZH2 or MUS81 expression correlated with chemoresistance and poorer outcomes in patients with BRCA2-mutated tumors.
  • * Ezh2 inhibition in a murine Brca2-/- breast cancer model induced acquired PARPi resistance.

Conclusions:

  • * EZH2 is a critical regulator of genomic stability at stalled replication forks, linking histone modifications to nuclease recruitment.
  • * The EZH2/MUS81 axis is a key determinant of PARPi sensitivity in BRCA2-deficient cancers.
  • * EZH2 expression serves as a predictive biomarker for response to chemotherapy in BRCA2-deficient tumors.

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