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J Biol Chem. 2018 Feb 16;293(7):2498-2509. doi: 10.1074/jbc.RA117.000498. Epub 2017 Dec 29.

Recruitment and allosteric stimulation of a histone-deubiquitinating enzyme during heterochromatin assembly.

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From the Department of Biochemistry and Molecular Genetics and.
Molecular Biology Program, University of Colorado, Denver-Anschutz Medical Campus, Aurora, Colorado 80045 and.
the Department of Biochemistry and Molecular Biology, Colorado State University, Fort Collins, Colorado 80523.
From the Department of Biochemistry and Molecular Genetics and


Heterochromatin formation in budding yeast is regulated by the silent information regulator (SIR) complex. The SIR complex comprises the NAD-dependent deacetylase Sir2, the scaffolding protein Sir4, and the nucleosome-binding protein Sir3. Transcriptionally active regions present a challenge to SIR complex-mediated de novo heterochromatic silencing due to the presence of antagonistic histone post-translational modifications, including acetylation and methylation. Methylation of histone H3K4 and H3K79 is dependent on monoubiquitination of histone H2B (H2B-Ub). The SIR complex cannot erase H2B-Ub or histone methylation on its own. The deubiquitinase (DUB) Ubp10 is thought to promote heterochromatic silencing by maintaining low H2B-Ub at sub-telomeres. Here, we biochemically characterized the interactions between Ubp10 and the SIR complex machinery. We demonstrate that a direct interaction between Ubp10 and the Sir2/4 sub-complex facilitates Ubp10 recruitment to chromatin via a co-assembly mechanism. Using hydrolyzable H2B-Ub analogs, we show that Ubp10 activity is lower on nucleosomes compared with H2B-Ub in solution. We find that Sir2/4 stimulates Ubp10 DUB activity on nucleosomes, likely through a combination of targeting and allosteric regulation. This coupling mechanism between the silencing machinery and its DUB partner allows erasure of active PTMs and the de novo transition of a transcriptionally active DNA region to a silent chromatin state.


SIR complex; chromatin; deubiquitylation (deubiquitination); epigenetics; heterochromatin; histone; sirtuin; ubiquitination; yeast

[Available on 2019-02-16]

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