Multivalent Histone and DNA Engagement by a PHD/BRD/PWWP Triple Reader Cassette Recruits ZMYND8 to K14ac-Rich Chromatin

Savitsky, P.; Krojer, T.; Fujisawa, Takao; Lambert, Jean-Philippe; Picaud, S.; Wang, Chen Yi; Shanle, Erin K.; Krajewski, Krzysztof; Friedrichsen, Hans; Kanapin, Alexander; Goding, Colin R.; Schapira, Matthieu; Samsonova, Anastasia; Strahl, Brian D.; Gingras, Anne‐Claude; Filippakopoulos, P.

doi:10.1016/j.celrep.2016.11.014

Cited by 84 publications

(147 citation statements)

References 44 publications

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“…ZMYND8 is a transcriptional repressor containing a bromodomain, PWWP and PHD chromatin-binding domains [184]. These domains are tandemly arranged (PHD-BRD-PWWP) so that ZMYND8 functions as a combinatorial reader of multiple histone marks, including H3K14Ac/H3K4me [183,184]. ZMYND8 is recruited to DSBs through direct interaction with H4K8Ac/K12Ac, a process dependent on Tip60 (for H4Ac) and the bromodomain of ZMYND8 [172].…”

Section: (C) H4ac and Bromodomainsmentioning

confidence: 99%

The tale of a tail: histone H4 acetylation and the repair of DNA breaks

Dhar¹,

Gürsoy-Yüzügüllü²,

Parasuram³

et al. 2017

Phil. Trans. R. Soc. B

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The ability of cells to detect and repair DNA double-strand breaks (DSBs) within the complex architecture of the genome requires co-ordination between the DNA repair machinery and chromatin remodelling complexes. This co-ordination is essential to process damaged chromatin and create open chromatin structures which are required for repair. Initially, there is a PARP-dependent recruitment of repressors, including HP1 and several H3K9 methyltransferases, and exchange of histone H2A.Z by the NuA4-Tip60 complex. This creates repressive chromatin at the DSB in which the tail of histone H4 is bound to the acidic patch on the nucleosome surface. These repressor complexes are then removed, allowing rapid acetylation of the H4 tail by Tip60. H4 acetylation blocks interaction between the H4 tail and the acidic patch on adjacent nucleosomes, decreasing inter-nucleosomal interactions and creating open chromatin. Further, the H4 tail is now free to recruit proteins such as 53BP1 to DSBs, a process modulated by H4 acetylation, and provides binding sites for bromodomain proteins, including ZMYND8 and BRD4, which are important for DSB repair. Here, we will discuss how the H4 tail functions as a dynamic hub that can be programmed through acetylation to alter chromatin packing and recruit repair proteins to the break site.This article is part of the themed issue 'Chromatin modifiers and remodellers in DNA repair and signalling'.

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Section: (C) H4ac and Bromodomainsmentioning

confidence: 99%

The tale of a tail: histone H4 acetylation and the repair of DNA breaks

Dhar¹,

Gürsoy-Yüzügüllü²,

Parasuram³

et al. 2017

Phil. Trans. R. Soc. B

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“…20 In addition to this, Gong and colleagues also described a similar role for JARID1A: this protein is recruited to the site of damage in a PARP1-dependent manner and its demethylating activity on pre-existing H3K4me3 is required for ZMYND8 recruitment to the site of damage, 21 which, in turn, allows NuRD complex association to initiate HR-related remodeling events. 22,23 In partial contrast with these observations, Penterling and colleagues suggested that JARID1A's role in DDR is not dependent on its catalytic activity. However, depletion of this protein enhances cells' sensitivity to irradiation-induced death.…”

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confidence: 95%

JARID1B expression and its function in DNA damage repair are tightly regulated by miRNAs in breast cancer

et al. 2019

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JARID 1B/ KDM 5B histone demethylase's mRNA is markedly overexpressed in breast cancer tissues and cell lines and the protein has been shown to have a prominent role in cancer cell proliferation and DNA repair. However, the mechanism of its post‐transcriptional regulation in cancer cells remains elusive. We performed a computational analysis of transcriptomic data from a set of 103 breast cancer patients, which, along with JARID 1B upregulation, showed a strong downregulation of 2 microRNAs (mi RNAs ), mir‐381 and mir‐486, potentially targeting its mRNA . We showed that both mi RNA s can target JARID 1B 3′ UTR and reduce luciferase's activity in a complementarity‐driven repression assay. Moreover, MCF 7 breast cancer cells overexpressing JARID 1B showed a strong protein reduction when transfected with mir‐486. This protein's decrease is accompanied by accumulation of DNA damage, enhanced radiosensitivity and increase of BRCA 1 mRNA , 3 features previously correlated with JARID 1B silencing. These results enlighten an important role of a mi RNA’ s circuit in regulating JARID 1B's activity and suggest new perspectives for epigenetic therapies.

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“…ZMYND8 is known to bind acetyl lysine 14 of histone H3 (H3K14ac) and acetyl lysine 16 of histone H4 (H4K16ac). 5,6 We found that hypoxia significantly increased occupancy of H3K14ac and H4K16ac at the HREs. Along with increased enrichment of H3K14ac and H4K16ac, ZMYND8 occupancy at the HREs was also elevated by hypoxia in breast cancer cells.…”

Section: Hypoxia-inducible Factor; Epigenetic Reader; Gene Regulationmentioning

confidence: 76%