Article

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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    • "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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    • "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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