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

Rondinelli et al. show that EZH2-mediated H3K27me3 at stalled replication forks recruits MUS81 nuclease to facilitate fork degradation. Loss of EZH2 contributes to PARPi resistance in BRCA2-deficient tumours. The emergence of resistance to poly-ADP-ribose polymerase inhibitors (PARPi) poses a threat...

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Published in:Nature cell biology Vol. 19; no. 11; pp. 1371 - 1378
Main Authors: Rondinelli, Beatrice, Gogola, Ewa, Yücel, Hatice, Duarte, Alexandra A., van de Ven, Marieke, van der Sluijs, Roxanne, Konstantinopoulos, Panagiotis A., Jonkers, Jos, Ceccaldi, Raphaël, Rottenberg, Sven, D’Andrea, Alan D.
Format: Journal Article
Language:English
Published: London Nature Publishing Group UK 01.11.2017
Nature Publishing Group
Subjects:
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631/337/1427
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96/1
Adenosine diphosphate
Analysis
Animals
Biomarkers
Biomarkers, Tumor - metabolism
BRCA mutations
BRCA1 protein
BRCA1 Protein - metabolism
BRCA2 protein
BRCA2 Protein - metabolism
Breast cancer
Breast Neoplasms - genetics
Breast Neoplasms - metabolism
Cancer
Cancer Research
Cell Biology
Cell Line
Cell Line, Tumor
Chemoresistance
Chemotherapy
Control stability
Deoxyribonucleic acid
Developmental Biology
DNA
DNA biosynthesis
DNA damage
DNA replication
DNA Replication - drug effects
DNA Replication - genetics
DNA-Binding Proteins - metabolism
Drug Resistance, Neoplasm - genetics
Endonucleases - metabolism
Enhancer of Zeste Homolog 2 Protein - metabolism
Female
Genetic aspects
Genomic Instability - drug effects
Genomic Instability - genetics
Genomics
HEK293 Cells
HeLa Cells
Histone H3
Histones
Histones - metabolism
Humans
letter
Life Sciences
Methylation
Methylation - drug effects
Mice
Mice, Nude
Nuclease
Patient outcomes
Physiological aspects
Poly(ADP-ribose) Polymerase Inhibitors - pharmacology
Recruitment
Replication
Replication forks
Ribose
Stabilization
Stem Cells
Tumors
United States
ISSN:1465-7392, 1476-4679, 1476-4679
Online Access:Get full text
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Summary:Rondinelli et al. show that EZH2-mediated H3K27me3 at stalled replication forks recruits MUS81 nuclease to facilitate fork degradation. Loss of EZH2 contributes to PARPi resistance in BRCA2-deficient tumours. 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 1 . Stabilization of stalled DNA replication forks is a recently identified PARPi-resistance mechanism that promotes genomic stability in BRCA1/2-deficient cancers 2 . 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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ISSN:1465-7392
1476-4679
1476-4679
DOI:10.1038/ncb3626