Human Molecular Genetics, Vol 8, 2515-2524, Copyright © 1999 by Oxford University Press
NS Heiss, A Girod, R Salowsky, S Wiemann, R Pepperkok and A Poustka
Mutations in the DKC1 gene are responsible for causing the bone marrow
failure syndrome, dyskeratosis congenita (DKC; OMIM 305000). The majority
of mutations identified to date are missense mutations and are clustered in
exons 3, 4 and 11. It is predicted that the corresponding protein dyskerin
is a nucleolar phosphoprotein which functions in both pseudo-uridylation
and cleavage of precursor rRNA. Dyskerin contains multiple putative nuclear
localization signals (NLSs) at the N-terminus (KKHKKKKERKS) and C-terminus
[KRKR(X)(17)KKEKKKSKKDKKAK(X)(17)- KKKKKKKKAKEVELVSE]. By fusing dyskerin
with the enhanced green fluorescent protein (EGFP) and by following a time
course of expression in mammalian cell lines, we showed that full-length
dyskerin initially localizes to the nucleoplasm and subsequently
accumulates in the nucleoli. A co-localization to the coiled bodies was
observed in some cells where dyskerin-EGFP had translocated to the
nucleoli. Analysis of a series of mutant constructs indicated that whereas
the most C- terminal lysine-rich clusters
[KKEKKKS-KKDKKAK(X)(17)KKKKKKKKAKEVELVSE] influence the rate of
nucleoplasmic and nucleolar accumulation, the KRKR sequence is primarily
responsible for the nuclear import. Nucleolar localization was maintained
when either the N- or C-terminal motifs were mutated, but not when all NLSs
were removed. We conclude that the intranuclear localization of dyskerin is
accomplished by the synergistic effect of a number of NLSs and that the
nucleolar localization signals are contained within the NLSs. Further,
examination of dyskerin-EGFP fusions mimicking mutations detected in
patients indicated that the intracellular mislocalization of dyskerin is
unlikely to cause DKC.
ARTICLES
Dyskerin localizes to the nucleolus and its mislocalization is unlikely to play a role in the pathogenesis of dyskeratosis congenita
Deutsches Krebsforschungszentrum (DKFZ), Department of Molecular Genome Analysis, Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany and
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