Poly(ADP-ribose) Polymerase 1 Is Inhibited by a Histone H2A Variant, MacroH2A, and Contributes to Silencing of the Inactive X Chromosome

Laval University, Quebec City, Quebec, Canada
Journal of Biological Chemistry (Impact Factor: 4.57). 05/2007; 282(17):12851-9. DOI: 10.1074/jbc.M610502200
Source: PubMed

ABSTRACT Poly(ADP-ribose) polymerase 1 (PARP-1) is a nuclear enzyme that is involved in modulating chromatin structure, regulation
of gene expression, and sensing DNA damage. Here, we report that PARP-1 enzymatic activity is inhibited by macroH2A, a vertebrate
histone H2A variant that is enriched on facultative heterochromatin. MacroH2A family members have a large C-terminal non-histone
domain (NHD) and H2A-like histone domain. MacroH2A1.2 and PARP-1 interact in vivo and in vitro via the NHD. The NHD of each macroH2A family member was sufficient to inhibit PARP-1 enzymatic activity in vitro. The NHD of macroH2A1.2 was a mixed inhibitor of PARP-1 catalytic activity, with affects on both catalytic activity and the
substrate binding affinity of PARP-1. Depletion of PARP-1 by RNA interference caused reactivation of a reporter gene on the
inactive X chromosome, demonstrating that PARP-1 participates in the maintenance of silencing. These results suggest that
one function of macroH2A in gene silencing is to inhibit PARP-1 enzymatic activity, and this may affect PARP-1 association
with chromatin.

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    • "The same study also showed that mH2A inhibited the enzyme activity of Parp - 1 . When somatic cells were treated with shRNA against Parp - 1 , together with 5 - azadC and TSA , about 7% of cells showed reactivation of a Xi - linked GFP reporter ( Nusinow et al . , 2007 ) . Cullin3 / Spop E3 ubiquitin ligase . Identified as proteins interacting with Bmi1 ( a PRC1 protein ) , the Cullin3 / Spop Ubiquitin E3 ligase was shown to have a link with XCI ( Hernandez - Munoz et al . , 2005 ) , Cullin3 / Spop ubiquitinate Bmi1 , and macroH2A1 . When cells were treated with 5 - azadC , TSA , and shRNA against Cul"
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    ABSTRACT: Each mammalian female cell transcriptionally inactivates one X chromosome to balance X-linked gene dosage between males and females. This phenomenon, called X chromosome inactivation, is a perfect epigenetic event, in which two chromosomes with identical DNA sequences are solely distinguished by epigenetic modifications. In this case, epigenetic marks, such as histone modifications, histone variants, DNA methylation, and ncRNAs, are all enriched on one chromosome, the inactive X chromosome (Xi), to establish its chromosome-wide gene silencing. At face value, it seems that the gene silencing mechanism of Xi is well understood. However, the "silence" of Xi in somatic cells is so tightly maintained that it remains largely intact even after almost all known epigenetic modifications are artificially depleted. To understand how the gene silence of Xi is maintained in soma is a major challenge in current research. We summarize the current knowledge related with this issue and discuss future research directions.
    genesis 11/2011; 49(11):821-34. DOI:10.1002/dvg.20792 · 2.04 Impact Factor
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    • "Further supporting a putative transcriptional repression role for macroH2A, the histone variant inactivates heat shock responsive genes through a repressive interaction with the poly (ADPribose ) polymerase-1 (PARP1), with PARP1 repression relieved upon release of macroH2A from the promoter region of these genes (Ouararhni et al., 2006). Inhibition of PARP1 by macroH2A also appears to play a role in X inactivation (Menissier de Murcia et al., 2003; Nusinow et al., 2007). Interestingly, the macro domain binds to ADP-ribose, the product of PARP1 activity, and some of its derivatives, suggesting that macroH2A responds to these enzymatic activities (Kustatscher et al., 2005; Timinszky et al., 2009). "
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    Developmental Cell 11/2010; 19(5):662-74. DOI:10.1016/j.devcel.2010.10.014 · 10.37 Impact Factor
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    • "However, it is interesting to hypothesize that the large macrodomain-containing nonhistone region of macroH2A1 plays a role in this process. This domain represents a platform that can (1) recruit chromatin-dependent transcriptional regulators (e.g., HP1b, HDAC1, and PARP-1) (Chakravarthy et al. 2005; Changolkar and Pehrson 2006; Ouararhni et al. 2006; Nusinow et al. 2007), (2) provide a novel platform for covalent modifications (e.g., S137 phosphorylation) (Bernstein et al. 2008), and (3) bind small molecule ligands (e.g., the NAD + metabolites poly[ADP-ribose], ADP-ribose, and O-acetyl-ADP-ribose, in the case of macroH2A1.1) (Kustatscher et al. 2005; Timinszky et al. 2009). "
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    ABSTRACT: MacroH2A1 is a histone variant that is enriched on the inactive X chromosome (Xi) in mammals and is postulated to play an important, but unknown, role in the repression of gene expression. Here we show that, although macroH2A1 marks repressed autosomal chromatin, it positively regulates transcription when located in the transcribed regions of a subset of its target genes. We used chromatin immunoprecipitation (ChIP) coupled with tiling microarrays (ChIP-chip) to determine the genomic localization of macroH2A1 in IMR90 human primary lung fibroblasts and MCF-7 breast cancer cells. The patterns of macroH2A1 deposition are largely similar across the autosomes of both cell lines. Our studies revealed a genomic localization pattern unique among histone variants; namely, the occupation by macroH2A1 of large chromatin domains (>500 kb in some cases) that contain repressive chromatin marks (e.g., histone H3 Lys 27 trimethylation). The boundaries of macroH2A1-containing domains tend to occur in promoter-proximal regions. Not all promoters, however, serve as macroH2A1 boundaries; many macroH2A1-containing chromatin domains invade the transcribed regions of genes whose products play key roles in development and cell-cell signaling. Surprisingly, the expression of a subset of these genes is positively regulated by macroH2A1. MacroH2A1 also plays a role in augmenting signal-regulated transcription, specifically for genes responsive to serum starvation. Collectively, our results document an unexpected role for macroH2A1 in the escape from heterochromatin-associated silencing and the enhancement of autosomal gene transcription.
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