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.