EZH2 Promotes Degradation of Stalled Replication Forks by Recruiting MUS81 Through Histone H3 Trimethylation

Overview

Journal Nat Cell Biol

Specialty Cell Biology

Date 2017 Oct 17

PMID 29035360

Citations 191

Authors

Beatrice Rondinelli

Ewa Gogola

Hatice Yucel

Alexandra A Duarte

Marieke van de Ven

Roxanne van der Sluijs

Panagiotis A Konstantinopoulos

Jos Jonkers

Raphael Ceccaldi

Sven Rottenberg

Alan D DAndrea

Affiliations

Soon will be listed here.

Abstract

The emergence of resistance to poly-ADP-ribose polymerase inhibitors (PARPi) poses a threat to the treatment of BRCA1 and BRCA2 (BRCA1/2)-deficient tumours. Stabilization of stalled DNA replication forks is a recently identified PARPi-resistance mechanism that promotes genomic stability in BRCA1/2-deficient cancers. Dissecting the molecular pathways controlling genomic stability at stalled forks is critical. Here we show that EZH2 localizes at stalled forks where it methylates Lys27 on histone 3 (H3K27me3), mediating recruitment of the MUS81 nuclease. Low EZH2 levels reduce H3K27 methylation, prevent MUS81 recruitment at stalled forks and cause fork stabilization. As a consequence, loss of function of the EZH2/MUS81 axis promotes PARPi resistance in BRCA2-deficient cells. Accordingly, low EZH2 or MUS81 expression levels predict chemoresistance and poor outcome in patients with BRCA2-mutated tumours. Moreover, inhibition of Ezh2 in a murine Brca2 breast tumour model is associated with acquired PARPi resistance. Our findings identify EZH2 as a critical regulator of genomic stability at stalled forks that couples histone modifications to nuclease recruitment. Our data identify EZH2 expression as a biomarker of BRCA2-deficient tumour response to chemotherapy.

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