The enigmatic role of H2Bub1 in cancer

Abstract

Edited by Wilhelm JustKeywords: H2B Monoubiquitination Chromatin Tumor suppressor Cancer Epigenetic a b s t r a c tThe post-translational modification of histone proteins plays an important role in controlling cell fate by directing essentially all DNA-associated nuclear processes. Misregulation and mutation of histone modifying enzymes is a hallmark of tumorigenesis. However, how these different epigenetic modifications lead to tumor initiation and/or progression remains poorly understood. Recent studies have uncovered a potential tumor suppressor role for histone H2B monoubiquitination (H2Bub1). Like many other histone modifications, H2Bub1 has diverse functions and plays roles both in transcriptional activation and repression as well as in controlling mRNA processing and directing DNA repair processes. Notably, H2Bub1 has been linked to transcriptional elongation and is preferentially found in the transcribed region of active genes. Its activity is intimately connected to active transcription and the transcriptional elongation regulatory protein cyclindependent kinase-9 (CDK9) and the facilitates chromatin transcription (FACT) complex. This review provides an overview of the current understanding of H2Bub1 function in mammalian systems with a particular emphasis on its role in cancer and potential options for exploiting this knowledge for the treatment of cancer.Ó 2012 Federation of European Biochemical Societies. Published by Elsevier B.V. Histone modificationsEpigenetic modifications are essential in controlling DNA associated processes such as cell type-specific gene expression, DNA replication and DNA repair. While much focus has been placed on DNA methylation, post-translational modifications of core histones also play an essential, but only poorly understood role in these processes. Chromatin is the composite of packaged nuclear DNA with its associated proteins. The basic unit of chromatin is the nucleosome containing approximately 147 bp of DNA wrapped around an octamer containing two each of histones H2A, H2B, H3 and H4. Histone octamers are then packaged into higher order chromatin structures by the interactions between individual nucleosomes and the binding of other proteins such as the linker histone H1, heterochromatin protein 1 (HP1), etc. Each of the core histones can be modified by a number of post-translational modifications such as the methylation of arginine and lysine residues, acetylation of lysine residues and phosphorylation of serine or threonine residues. Modifications of the core histones have been hypothesized to make up a ''histone code'' which controls DNAassociated processes in different ways according to the repertoire of modifications present at a given chromatin region [1,2]. Furthermore, a number of other post-translational modifications of histones such as formylation [3,4], sumoylation [5], crotonylation[6], ADP-ribosylation [7], etc., have been identified, but their functions remain mostly enigmatic.In addition to the more common modifications like methylation, acetylation ...

H2B monoubiquitination: t'ub or not t'ub for inducible enhancers

“…10 This was even apparent in our own data as we observed that H2Bub1 is associated with active enhancers despite a repressive action on them. 12 Interestingly, a similar apparent contradiction between activation and repressive roles also exists for H2A.Z.…”

Cotranscriptional histone H2B monoubiquitylation is tightly coupled with RNA polymerase II elongation rate

“…Aberrant H2Bub1 levels can affect development (Wright et al 2011), apoptosis (Walter et al 2010), stem cell differentiation (Buszczak et al 2009;Fuchs et al 2012;Karpiuk et al 2012), viral infection outcome (Sarkari et al 2009;Fonseca et al 2012), and cell cycle progression (Hwang and Madhani 2009) and can promote cancer Blank et al 2012;Johnsen 2012;. Several mechanisms have been proposed to underlie the ability of H2Bub1 to exert those diverse effects, including impact on higher-order chromatin organization (Fierz et al 2011), altered nucleosome stability (Chandrasekharan et al 2009), regulation of H2A-H2B dimer displacement (Pavri et al 2006), and modulation of the recruitment of specific factors to chromatin (Shema-Yaacoby et al 2013).…”

Aggregation of Polyglutamine-expanded Ataxin 7 Protein Specifically Sequesters Ubiquitin-specific Protease 22 and Deteriorates Its Deubiquitinating Function in the Spt-Ada-Gcn5-Acetyltransferase (SAGA) Complex

“…7). Because H2Bub is important for both transcription initiation and elongation (23,24), dysfunction of the DUBm in the SAGA complex caused by polyQexpanded Atx7 may be a major source for transcriptional dysregulation in SCA7 disease.…”

“…GCN5 endows the histone acetyltransferase activity of SAGA (18), whereas USP22, together with Atx7, Atx7L3, and ENY2, assembles into the deubiquitination module (DUBm), which is responsible for deubiquitinating monoubiquitinated histone H2A (H2Aub) and H2B (H2Bub) (19 -22). Both H2Aub and H2Bub participate in many cellular processes, including transcription initiation and elongation, gene silencing, and DNA repair (23,24).…”