The “Fifth” RNA Nucleotide: A Role for Ribosomal RNA Pseudouridylation in Control of Gene Expression at the Translational Level - Biophysical Approaches to Translational Control of Gene Expression - page 269

clinically milder forms of the disease have also been described. These include
autosomal-dominant DC (AD-DC), caused predominantly by mutations in genes
implicated in telomere maintenance, including the telomerase RNA component
(TERC) (Vulliamy et al. 2001 ) and the telomerase reverse transcriptase (TERT)
(Armanios et al. 2005 ), and autosomal-recessive DC (AR-DC), resulting from muta-
tions in the H/ACA snoRNP components NHP2 and NOP10 (Vulliamy et al. 2008 ;
Walne et al. 2007 ). As mentioned earlier (see Sect. 13.3 ), in addition to associating
with H/ACA snoRNAs, dyskerin also associates with H/ACA scaRNAs including
TERC (Meier 2006 ), implicating it in a broad range of cellular processes such as
rRNA pseudouridylation, splicing, and telomere maintenance. Importantly, defec-
tive telomere maintenance is evident in all forms of DC and several studies indicate
that telomere shortening may contribute to some of the clinical features observed in
X-DC (Batista et al. 2011 ; Bessler et al. 2004 ; Dokal 2000 ; Mitchell et al. 1999 ;
Vulliamy et al. 2006 ). Thus, given the multifunctional role of dyskerin within cells,
it is plausible to speculate that the severity of X-DC may stem from multiple molec-
ular and cellular defects.
Strikingly, more than 50 X-DC-associated missense mutations in DKC1 have
been annotated to date ( http://telomerase.asu.edu/diseases.html ), the majority of
which cluster in the N and C termini of the protein. Tertiary structure analysis indi-
cates that these two regions form the PUA domain of the protein (Rashid et al.
2006 ), which is critical for its binding to box H/ACA snoRNAs (see Sect. 13.3.3 ).
Thus, it seems likely that mutations within the PUA domain of dyskerin may disrupt
H/ACA snoRNA stability and function leading to site-specific reductions in rRNA
pseudouridylation. Indeed, introduction of two DKC1 mutations frequently found
in X-DC patients into murine embryonic stem cells results in reduced expression of
specific H/ACA snoRNAs along with reductions in pseudouridylation of the corre-
sponding sites on rRNA (Mochizuki et al. 2004 ) . These fi ndings support the possi-
bility that X-DC patients may also harbor reductions in a subset of H/ACA snoRNAs
and subsequently decreased Y modifications at corresponding target residues. While
investigations to explore this possibility are currently underway, it would be infor-
mative to assess whether specific loss of Y residues in distinct regions of rRNA may
contribute to particular disease phenotypes. Important functional insights into the
mechanisms underlying some of the pathological features present in X-DC have
been uncovered utilizing Dkc1 m mice (Ruggero et al. 2003 ) . In these mice, reduc-
tions in rRNA pseudouridylation are present prior to disease onset when telomeres
are unperturbed, suggesting that rRNA pseudouridylation may contribute to some
of the clinical features present in X-DC. Importantly, the first translational targets
identified downstream of reductions in rRNA pseudouridylation levels (see
Sect. 13.4.2 ) were also recapitulated in primary X-DC patient cells (Bellodi et al.
2010a ; Yoon et al. 2006 ), indicating that defects in IRES-dependent translation may
contribute to the disease.
How does impaired IRES-dependent translation in X-DC potentially contribute
to the tissue-specific pathological features observed in this disease? IRES-dependent
translation is a fine-tuning mechanism that can regulate gene expression during key
cellular conditions including quiescence, survival, and differentiation (Iglesias-
Serret et al. 2003 ; Krichevsky et al. 1999 ; Miskimins et al. 2001 ; Pyronnet et al.