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SAGA-Dependent Histone H2Bub1 Deubiquitination Is Essential for Cellular Ubiquitin Balance during Embryonic Development

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posted on 20.09.2022, 02:54 authored by Farrah El-SaafinFarrah El-Saafin, D Devys, SA Johnsen, SD Vincent, L Tora
Ubiquitin (ub) is a small, highly conserved protein widely expressed in eukaryotic cells. Ubiquitination is a post-translational modification catalyzed by enzymes that activate, conjugate, and ligate ub to proteins. Substrates can be modified either by addition of a single ubiquitin molecule (monoubiquitination), or by conjugation of several ubs (polyubiquitination). Monoubiquitination acts as a signaling mark to control diverse biological processes. The cellular and spatial distribution of ub is determined by the opposing activities of ub ligase enzymes, and deubiquitinases (DUBs), which remove ub from proteins to generate free ub. In mammalian cells, 1–2% of total histone H2B is monoubiquitinated. The SAGA (Spt Ada Gcn5 Acetyl-transferase) is a transcriptional coactivator and its DUB module removes ub from H2Bub1. The mammalian SAGA DUB module has four subunits, ATXN7, ATXN7L3, USP22, and ENY2. Atxn7l3−/− mouse embryos, lacking DUB activity, have a five-fold increase in H2Bub1 retention, and die at mid-gestation. Interestingly, embryos lacking the ub encoding gene, Ubc, have a similar phenotype. Here we provide a current overview of data suggesting that H2Bub1 retention on the chromatin in Atxn7l3−/− embryos may lead to an imbalance in free ub distribution. Thus, we speculate that ATXN7L3-containing DUBs impact the free cellular ub pool during development.

Funding

This study was supported by grants from, Agence Nationale de la Recherche (ANR) PICen-19-CE11-0003-02 and EpiCAST-19-CE12-0029-01 grants, NIH 1R01GM131626-01 and NIH MIRA (R35GM139564) grants, `Fondation pour la Recherche Medicale' (FRM) association (EQU-202103012631) grant (to LT) and ANR-20-CE12-0014-02 grant (to DD), and an ANR-10-LABX-0030-INRT grant under the frame program Investissements d'Avenir ANR-10-IDEX-0002-02 (to IGBMC).

History

Publication Date

05/07/2022

Journal

International Journal of Molecular Sciences

Volume

23

Issue

13

Article Number

7459

Pagination

12p.

Publisher

MDPI

ISSN

1661-6596

Rights Statement

© 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).