Human Molecular Genetics Advance Access originally published online on November 12, 2003
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Human Molecular Genetics, 2004, Vol. 13, No. 1 15-23
DOI: 10.1093/hmg/ddh006
© 2004 Oxford University Press
Reduced histone biotinylation in multiple carboxylase deficiency patients: a nuclear role for holocarboxylase synthetase
1Department of Biochemistry and Molecular Biology, University of Calgary, Calgary, Alberta, Canada T2N 4N1 and 2McGill University-Montreal Children's Hospital Research Institute, Montreal, Quebec, Canada H3Z 2Z3
Received July 13, 2003; Accepted October 29, 2003
The attachment of biotin to apocarboxylases is catalyzed by holocarboxylase synthetase (HCS). An inherited deficiency of HCS results in the disorder ‘multiple carboxylase deficiency’, which is characterized by reduced activity of all biotin-dependent carboxylases. Here we show that the majority of HCS localizes to the nucleus rather than the cytoplasm based on immunofluorescence studies with antibodies to peptides and full length HCS and on the expression of recombinant HCS. Subnuclear fractionations indicate that HCS is associated with chromatin and the nuclear lamina, the latter in a discontinuous distribution in high salt-extracted nuclear membranes. During mitosis, HCS resolves into ring-like particles which co-localize with lamin B. Nuclear HCS retains its biotinylating activity and was shown to biotinylate purified histones in vitro. Significantly, fibroblasts from patients with HCS deficiency are severely deficient in histone biotinylation in addition to the deficiency of carboxylase activities. We propose that the role of HCS in histone modification may be linked to the participation of biotin in the regulation of gene expression or cell division and that affected patients may have additional disease beyond that due to the effect on carboxylases.
* To whom correspondence should be addressed at: Department of Biochemistry and Molecular Biology, University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta, Canada T2N 4N1. Tel: +1 4032202268; Email: rgravel{at}ucalgary.ca
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