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. 2008 Apr 22:3:8.
doi: 10.1186/1747-1028-3-8.

The many faces of ubiquitinated histone H2A: insights from the DUBs

Joseph Ha Vissers #  1 , Francesco Nicassio #  2 , Maarten van Lohuizen  1 , Pier Paolo Di Fiore  2   3   4 , Elisabetta Citterio  1
Affiliations

The many faces of ubiquitinated histone H2A: insights from the DUBs

Joseph Ha Vissers et al. Cell Div. .

Abstract

Monoubiquitination of H2A is a major histone modification in mammalian cells. Understanding how monoubiquitinated H2A (uH2A) regulates DNA-based processes in the context of chromatin is a challenging question. Work in the past years linked uH2A to transcriptional repression by the Polycomb group proteins of developmental regulators. Recently, a number of mammalian deubiquitinating enzymes (DUBs) that catalyze the removal of ubiquitin from H2A have been discovered. These studies provide convincing evidence that H2A deubiquitination is connected with gene activation. In addition, uH2A regulatory enzymes have crucial roles in the cellular response to DNA damage and in cell cycle progression. In this review we will discuss new insights into uH2A biology, with emphasis on the H2A DUBs.

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Figures

Figure 1
Figure 1
Crosstalk between monoubiquitinated H2A (uH2A) and other histone modifications. Functional implications in transcription regulation (A-C), DNA damage response (D) and cell cycle progression (E) are illustrated. A. H3/H4 acetylation stimulates de-ubiquitination of uH2A by 2A-DUB in vitro, linking these modifications in the regulation of transcription. B. uH2A prevents H3K4 methylation by MLL3 in vitro. This is possibly one of the mechanisms by which uH2A negatively affects transcription initiation. C. Elevated global levels of uH2A correlate with low phosphorylation of linker histone H1, as observed upon knockdown of one of the H2A DUBs, 2A-DUB. Phosphorylation of H1 is thought to favor enhanced chromatin dissociation of this histone. uH2A might, by promoting/stabilizing H1 association with the nucleosome, diminish chromatin dynamics, thereby negatively affecting transcription. D. Histone phosphorylation and ubiquitination synergize in DNA damage signaling upon ionizing radiation (IR). Upon IR, phosphorylation of H2AX leads to recruitment and phosphorylation of MDC1. Phosphorylated MDC1 recruits RNF8 through its FHA domain. RNF8 subsequently polyubiquitinates H2A and H2AX. Also, TIP60-dependent acetylation of H2AX on K5 favors H2AX polyubiquitination upon IR. E. uH2A inhibits H3 S10 phosphorylation by AuroraB kinase in vitro, providing a potential mechanism for regulation of G2/M transition in vivo. The labels "Ub", "Ac", "Me" and "P" refer to monoubiquitination, acetylation, di- and trimethylation, and phosphorylation respectively.
Figure 2
Figure 2
Models for regulation of transcription by monoubiquitinated H2A. A. uH2A inhibits RNA polymerase II initiation in vitro through a crosstalk with H3K4 methylation. uH2A prevents H3K4 methylation by the MLL3 histone methyltransferase. The enzymatic removal of ubiquitin from H2A by USP21 can positively influence H3K4 methylation by the methyltransferase. This would allow H3K4 methylation, which is a prerequisite for initiation of gene transcription. B. At bivalent promoters uH2A and H3K4 Me coexist. At these promoters, transcription initiation occurs despite the presence of uH2A. C. uH2A might inhibit transcription elongation or the transition from initiation to elongation by preventing association of the FACT elongation factor. In addition, uH2A might regulate elongation by recruiting inhibitory factors and/or affecting higher order chromatin association.
Figure 3
Figure 3
Signaling network at Ionizing Radiation Induced Nuclear Foci (IRIF). A. Early after IR, damaged DNA triggers ATM activation, which consequently phosphorylates H2AX near the break sites and MDC1. RNF8 is recruited to IRIF through binding to phosphorylated MDC1. RNF8 locally ubiquitinates H2A, H2AX and possibly other yet unidentified proteins ('X'). B. RNF8-dependent ubiquitin conjugation is required for recruitment of 53BP1 and BRCA1. BRCA1 is present in a protein complex containing BARD1, Abraxas/CCDC98, BRCC36 and RAP80. Ubiquitin binding by RAP80 is required for BRCA1 recruitment. However, the nature of the ubiquitinated substrate RAP80 binds to (histones or other proteins), is still unclear. In addition to BRCA1, ubiquitination allows recruitment of 53BP1 (which binds to methylated H3/H4) through a yet unknown mechanism. C. IRIF disassembly may involve dephosphorylation of γH2AX by PP2A. The DUB USP3 is a candidate to remove conjugated ubiquitin at IRIF.
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