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J. Biol. Chem., Vol. 276, Issue 40, 37161-37165, October 5, 2001
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From the Protein L-isoaspartate
O-methyltransferase (PIMT) is postulated to repair
Structural Integrity of Histone H2B in Vivo Requires
the Activity of Protein L-Isoaspartate
O-Methyltransferase, a Putative Protein Repair
Enzyme*
,,¶
Department of Molecular Biology and
Biochemistry, University of California, Irvine, California 92697 and
the § Section of Rheumatology, Yale University School of
Medicine, New Haven, Connecticut 06510
-aspartyl linkages (isoaspartyl (isoAsp)) that accumulate at
certain Asp-Xaa and Asn-Xaa sites in association with protein aging and
deamidation. To identify major targets of PIMT action we cultured rat
PC12 cells with adenosine dialdehyde (AdOx), a methyltransferase
inhibitor that promotes accumulation of isoAsp in vivo.
Subcellular fractionation of AdOx-treated cells revealed marked
accumulation of isoAsp in a 14-kDa nuclear protein. Gel electrophoresis
and chromatography of nuclei 3H-methylated in
vitro by PIMT revealed this protein to be histone H2B. The isoAsp
content of H2B in AdOx-treated cells was ~18 times that in control
cells, although no isoAsp was seen in other core histones, regardless
of treatment. To confirm the relevance and specificity of this effect,
we measured isoAsp levels in histones from brains of PIMT knockout
mice. IsoAsp was found at near stoichiometric levels in H2B extracted
from knockout brains and was at least 80 times greater than that in H2B
from normal mice. Little or no isoAsp was detected in H2A, H3, or H4
from mice of either genotype. Accumulation of isoAsp in histone H2B may
disrupt normal gene regulation and contribute to the reduced life span
that characterizes PIMT knockouts. In addition to disrupting protein
function, isoAsp has been shown to trigger immunity against
self-proteins. The propensity of H2B to generate isoAsp in
vivo may help explain why this histone in particular is found as
a major antigen in autoimmune diseases such as lupus erythematosus.
*
This work was supported by National Institutes of Health
Grant NS17269 (to D. W. A.), by the Arthritis Foundation, the Ethel F. Donaghue Foundation, and National Institutes of Health Grant AI36529
(to M. J. M.), and by National Institutes of Health Postdoctoral Fellowship AR47759 (to H. A. D.).The costs of publication of this article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
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