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

Nature cell biology (2017-10-17)
Beatrice Rondinelli, Ewa Gogola, Hatice Yücel, Alexandra A Duarte, Marieke van de Ven, Roxanne van der Sluijs, Panagiotis A Konstantinopoulos, Jos Jonkers, Raphaël Ceccaldi, Sven Rottenberg, Alan D D'Andrea
RÉSUMÉ

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

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5-Chloro-2′-deoxyuridine, thymidine analog
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Magnesium methyl carbonate solution, 2.0 M in DMF