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

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 (2017). EZH2 promotes degradation of stalled replication forks by recruiting MUS81 through histone H3 trimethylation. Nature cell biology, 19(11), pp. 1371-1378. Nature Publishing Group 10.1038/ncb3626

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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 Brca2breast 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.

Item Type:

Journal Article (Original Article)

Division/Institute:

05 Veterinary Medicine > Research Foci > Host-Pathogen Interaction
05 Veterinary Medicine > Department of Infectious Diseases and Pathobiology (DIP) > Institute of Animal Pathology
05 Veterinary Medicine > Department of Infectious Diseases and Pathobiology (DIP)

UniBE Contributor:

Rottenberg, Sven

Subjects:

500 Science > 570 Life sciences; biology
600 Technology > 610 Medicine & health
600 Technology > 630 Agriculture

ISSN:

1465-7392

Publisher:

Nature Publishing Group

Language:

English

Submitter:

Achim Braun Parham

Date Deposited:

08 May 2018 15:27

Last Modified:

23 Oct 2019 09:24

Publisher DOI:

10.1038/ncb3626

PubMed ID:

29035360

BORIS DOI:

10.7892/boris.112032

URI:

https://boris.unibe.ch/id/eprint/112032

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