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Nat Cell Biol. 2017 Nov;19(11):1371-1378. doi: 10.1038/ncb3626. Epub 2017 Oct 16.

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

Author information

1
Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02215, USA.
2
Center for DNA Damage and Repair, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02215, USA.
3
Division of Molecular Pathology and Cancer Genomics Netherlands, The Netherlands Cancer Institute, Amsterdam 1066 CX, the Netherlands.
4
Mouse Clinic for Cancer and Aging (MCCA), Preclinical Intervention Unit, The Netherlands Cancer Institute, Amsterdam 1066 CX, the Netherlands.
5
University of Amsterdam, Amsterdam 1012 WX, the Netherlands.
6
Department of Medical Oncology, Medical Gynecologic Oncology Program, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02215, USA.
7
Institute of Animal Pathology, Vetsuisse Faculty, University of Bern, Bern 3012, Switzerland.

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.

PMID:
29035360
DOI:
10.1038/ncb3626
[Indexed for MEDLINE]
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