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Blood First Edition Paper, prepublished online February 28, 2006; DOI 10.1182/blood-2005-12-4831
BLOOD PERSPECTIVE:
Ribosomes and Marrow Failure: Coincidental Association or Molecular Paradigm?
Johnson M. Liu1,2 and Steven R. Ellis3
1
Feinstein Institute for Medical Research, Manhasset, NY 11030, and 2Schneider
Children’s Hospital, New Hyde Park, NY 11040
3
Department of Biochemistry and Molecular Biology, University of Louisville School of
Medicine, Louisville, KY 40292
Correspondence to:
Johnson M. Liu, MD
Head, Les Nelkin Memorial Pediatric Oncology Laboratory
Schneider Children’s Hospital
Pediatric Hematology/Oncology & Stem Cell Transplantation
New Hyde Park, NY 11040
718-470-7174, phone
718-470-4843, fax
[email protected]
Copyright © 2006 American Society of Hematology
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ABSTRACT
Gene products mutated in the inherited bone marrow failure syndromes dyskeratosis
congenita (DC), cartilage-hair hypoplasia (CHH), Diamond-Blackfan anemia (DBA), and
Shwachman-Diamond syndrome (SDS), are all predicted to be involved in different
aspects of ribosome synthesis. At this moment, however, it is unclear whether this link
indicates a causal relationship. Although defective ribosome synthesis may contribute to
each of these bone marrow failure syndromes (and perhaps others), precisely which
feature of each disease is a consequence of failure to produce adequate amounts of
ribosomes is obscured by the tendency of each gene product to have extraribosomal
functions. Delineation of the precise role of each gene product in ribosomal biogenesis
and in hematopoietic development may have both therapeutic and prognostic importance
and perhaps even direct the search for new bone marrow failure genes.
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Inherited bone marrow failure syndromes, including dyskeratosis congenita (DC),
cartilage-hair hypoplasia (CHH), Diamond-Blackfan anemia (DBA), and ShwachmanDiamond syndrome (SDS), have long fascinated and challenged geneticists and
hematologists. This heterogeneous group of disorders is characterized by bone marrow
failure and the variable presence of congenital anomalies and cancer predisposition
(Table 1). While there has been rapid progress in identifying gene defects in nearly all
the disorders, understanding the molecular pathophysiology has lagged behind in most
instances. Intriguingly, genes mutated in many of these disorders encode factors
involved in ribosome synthesis, suggesting a link between this fundamental cellular
process and marrow failure. In this Perspective, we wish to define this association and
critically assess its validity in the light of new research.
Broadly speaking, the genes mutated in the inherited marrow failure syndromes
(reviewed in Lipton JM, Liu JM, and Vlachos A, manuscript submitted) have widely
disparate functions (Fanconi anemia genes, c-MPL, GFI1, ELA2, RUNX1, HOXA11,
GATA1, and others) without an obvious molecular interrelationship. By contrast, genes
mutated in X-linked DC1, CHH2, DBA3, and SDS4 all are predicted to be involved in
aspects of ribosome synthesis. Complicating this picture, however, is the fact that some
of the factors encoded by these genes are multifunctional, influencing one or more critical
cellular process in addition to ribosome synthesis. The most extensively studied bone
marrow failure syndrome from this perspective is X-linked DC, which is caused by
mutations in DKC1 (its encoded protein also known as dyskerin)1. Dyskerin is a putative
pseudouridyl synthase found in so-called H/ACA ribonucleoprotein complexes involved
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in ribosomal RNA (rRNA) modification. Since its discovery, dyskerin has also been
shown to be a component of other ribonucleoprotein complexes including telomerase5. A
similarly complex picture is emerging for CHH. The gene affected in CHH is RMRP,
which encodes the RNA component of RNase MRP (ribonuclease mitochondrial RNA
processing)2. RNase MRP is a multifunctional ribonucleoprotein complex involved in
cleaving rRNA precursors, processing of RNA primers used in mitochondrial DNA
replication, and the turnover of certain cell cycle-regulated mRNAs. The only gene
linked to DBA to date encodes ribosomal protein S19 (RPS19)3, which in yeast is
required for the maturation of 40S ribosomal subunits6. Here again, the human RPS19
protein has been proposed to have a function outside of this role7. Finally, several studies
have suggested that SBDS, mutations in which cause SDS4, encodes a protein involved in
ribosome synthesis8,9. Thus, although defective ribosome synthesis may contribute to
each of the bone marrow failure syndromes listed above, precisely which feature, if any,
of each disease is a consequence of failure to produce adequate amounts of ribosomes is
obscured by the tendency of each gene product to have extraribosomal functions (Fig. 1).
Ribosome Synthesis
The human ribosome is comprised of 4 ribosomal RNAs and a minimum of 80 different
ribosomal proteins. In addition to these structural components of the ribosome, there are
well over 100 additional factors involved in its biosynthesis10. These factors include
components of the RNA polymerase I transcriptional machinery, small nucleolar
ribonucleoprotein complexes involved in rRNA modification, a host of RNA helicases
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and other chaperone-like factors, nucleases, factors involved in nucleolar-cytoplasmic
transport, and structural components of the nucleolus. In yeast, the genes encoding the
majority of these factors are essential or cause significant growth defects when mutated,
indicating that they play a critical role in cell growth and division. Collectively, these
genes represent hundreds of potential target loci that when mutated may contribute to
human disease, making it imperative that we understand the pathophysiology underlying
the handful of human disorders currently linked to factors involved in ribosome
synthesis.
Many of the structural components of the ribosome, as well as additional biosynthetic
factors, have been shown to possess extraribosomal functions, ranging from roles in
replication and DNA repair to serving as receptors on the cell surface11. More recently,
an emerging body of data has linked specific ribosomal proteins to active roles in cellular
stress response12,13, proliferation14 and apoptosis15. The challenge in studying these
factors and their roles in human disease is sorting out their more general roles in
modulating protein synthetic capacity from functions more specific to a given factor, a
challenge further complicated by the diverse and variable array of clinical phenotypes
observed in the bone marrow failure syndromes discussed. Here we summarize some of
the current approaches being used to mechanistically dissect these disorders and suggest
possible venues for future research.
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DKC1 and X-Linked DC: Importance of Additional Disease-Linked Genes
We begin our analysis with X-linked dyskeratosis congenita (DC), which may serve as a
model wherein ribosomal dysfunction plays a role in bone marrow failure but is clearly
not the sole explanation. Ectodermal dysplasia and hematopoietic failure characterize
DC (reviewed in 16). In addition to the classic triad of abnormal skin pigmentation,
dystrophic nails and leukoplakia of mucous membranes, there are a number of other
somatic abnormalities17. The most common of these are epiphora, developmental delay,
pulmonary disease, short stature, esophageal webs, dental caries, tooth loss, premature
gray hair and hair loss. Pancytopenia is the hematologic hallmark of DC, and
approximately 50% of patients develop severe aplastic anemia and greater than 90% of
individuals at least a single cytopenia by 40 years of age.
Dyskeratosis congenita is most commonly inherited as an X-linked recessive disorder,
although autosomal dominant (AD-DC) and recessive (AR-DC) forms exist. The gene
responsible for the X-linked form was subsequently identified as DKC11. DKC1 encodes
dyskerin, a nucleolar protein that is one of four proteins associated with small nucleolar
ribonucleoprotein particles (snoRNPs) involved in rRNA maturation. Dyskerin
associates with the H/ACA (referring to characteristic short snoRNA sequences) class of
snoRNPs, which function in the pseudouridylation of rRNAs. Structural similarities
between dyskerin and yeast and bacterial pseudouridine synthases suggested that
dyskerin might be the active human pseudouridine synthase in the H/ACA complexes.
At the time of its discovery, this was the only known function of dyskerin thus leading to
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the inference that defects in ribosome synthesis, resulting from failure to properly modify
rRNA, are responsible for the manifestations of X-linked DC (Fig. 2).
Soon thereafter however, it became clear that dyskerin had other functions within cells.
Most importantly, dyskerin was found to be associated with the telomerase complex5.
The telomerase ribonucleoprotein complex, which is at times nucleolar, includes the
telomerase reverse transcriptase TERT and the telomerase RNA component TERC,
which acts as a template for the synthesis of the TTAGGG telomere repeats at the ends of
chromosomes. Telomeres protect the ends of chromosomes from degradation and
aberrant fusion events. TERC has an H/ACA-like domain and is associated with
dyskerin, GAR1, NOP10, and NHP2. Here, dyskerin appears to serve as a structural
component of the telomerase complex in contrast to its proposed role in the rRNAmodifying snoRNPs, as telomerase has no pseudouridylation target. With the discovery
that cells from patients with X-linked DC and AD-DC exhibit shortened telomeres18 and
the subsequent identification of causative mutations in TERC in AD-DC19, it was
presumed that defective telomerase activity, rather than impaired ribosomal maturation,
underlies the bone marrow failure seen in DC. Mutations in the TERT reverse
transcriptase gene have also been identified in aplastic anemia patients with short
telomeres, further implicating the telomerase pathway20.
Although the pendulum has swung away from ribosome synthesis and towards telomere
maintenance as explaining DC pathophysiology, the observation that the X-linked form
of the disease is more severe than the autosomal dominant form leaves open the
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possibility that an effect on ribosome synthesis may contribute to phenotypic outcome.
An extremely severe variant of DC known as Hoyeraal-Hreidarsson syndrome, which
leads to aplastic anemia, immunodeficiency, and cerebellar hypoplasia, is also caused by
mutations in DKC1, demonstrating that allelic differences in the same protein could lead
to more severe phenotypes21. We are also left with the puzzling features of the dyskerin
hypomorphic mouse model22, which displays some of the clinical features of DC prior to
the onset of significant telomere shortening. That these mice display defects in ribosome
synthesis suggests there may be some overlap in phenotype associated with defects in
ribosome synthesis and telomere maintenance. In addition, two dyskerin patient
mutations introduced into murine embryonic stem cells caused defective
pseudouridylation and decreased pre-rRNA processing, but only one of the two mutations
affected telomerase activity23. Thus, in yeast24, Drosophila25, and two different mouse
models, defects in dyskerin orthologs lead to a reduced rate of production of mature
rRNAs and accumulation of unprocessed precursor molecules. Collectively, these data
argue for involvement of both ribosome deficiency and telomerase dysfunction in DC
pathophysiology, with the contribution of each possibly dependent on the particular
mutation site within dyskerin. The crystal structure of the dyskerin-NOP10-GAR1
complex has recently been deduced26, which identifies a dyskerin domain within which
most DC mutations cluster. Current efforts employing detailed genotype/phenotype
correlations may assist in clarifying the relative contributions of ribosome synthesis and
telomere maintenance to the clinical features of DC.
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RMRP and Cartilage Hair Hypoplasia: Genotype/Phenotype Relationships
Cartilage-hair hypoplasia (CHH), also known as metaphyseal chondrodysplasia
McKusick type, was first described by Victor McKusick as a form of dwarfism in the
Amish27. CHH is an autosomal recessive disorder characterized by cartilage/skeletal
defects with short stature, fine sparse blond hair, and hypoplastic anemia. The anemia,
while typically mild, can be persistent and severe as in DBA28. CHH is also associated
with defective cellular immunity29, gastrointestinal dysfunction30, and a predisposition to
cancer (primarily lymphoma)31. Mutations in the untranslated RMRP gene were found to
cause CHH, with an ancient founder mutation in Finland2.
RMRP encodes the RNA component of the ribonuclease mitochondrial RNA processing
(RNase MRP) complex and is classified as a small nucleolar RNA (RMRP and the
previously mentioned TERC are the two only known non-mitochondrial examples of
RNA genes that when mutated lead to disease). In yeast, the RMRP ortholog NME1
(nuclear mitochondrial endonuclease-1) has multiple functions and is essential for
viability32. First, it functions in mitochondrial DNA replication by cleaving RNA primers
associated with nascent organelle DNA33. Second, some nme1 mutants exhibit a late
mitotic cell cycle arrest associated with increased cyclin B2 mRNA levels (normally, the
RNase MRP complex cleaves the 5’ untranslated region of cyclin B2 mRNA)34. Third,
RNase MRP plays a role in ribosomal RNA processing35. In both yeast and humans,
RNase MRP cleaves pre-rRNA within ITS1, influencing the maturation of the 5 end of
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5.8S rRNA (Fig. 2). Consistent with this latter function, RNase MRP is mainly located in
the nucleoli packaged as one of the snoRNPs. In humans, the RNase MRP complex
consists of the RNA component and at least 10 protein subunits36, of which 8 are shared
with ribonuclease P, involved in tRNA precursor maturation.
Recent work has suggested that it is the function of RMRP in cell cycle-regulated mRNA
turnover that underlies the bone marrow failure seen in CHH37. This conclusion is
supported by the discovery of novel RMRP mutations that lead to another autosomal
recessive growth disorder known as anauxetic dysplasia (AD), which is characterized by
extreme short stature, hypodontia, and mild mental retardation. While the growth
abnormalities in anauxetic dysplasia are reminiscent of those in CHH, hypoproliferative
bone marrow dysfunction and cancer susceptibility are seen only in CHH and not
anauxetic dysplasia. In vitro studies have shown that human fibroblasts overexpressing
the CHH founder mutation +70AJG exhibit both impaired rRNA endonucleolytic
cleavage and cyclin B2 mRNA cleavage (and hence increased cyclin B2 mRNA levels),
whereas cells overexpressing anauxetic dysplasia mutations exhibited only rRNA
cleavage abnormalities37. These genotype/phenotype studies imply that while RMRP
mutations can disrupt 5.8S rRNA maturation (and hence 60S ribosomal assembly)
resulting in some of the clinical features of CHH, it is likely the concurrent disruption of
cyclin B2 mRNA degradation and mitotic delay that explains the bone marrow failure
phenotype in CHH (Fig. 1).
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RPS19 and DBA: Focus Remains on Ribosomes
We now turn our focus to DBA, currently the only known human disease caused by
defects in a structural component of the ribosome, namely RPS19. DBA is a pure red cell
aplasia predominantly seen in infancy and childhood. In addition to anemia, other
significant cytopenias have been reported38,39. An elevated erythrocyte adenosine
deaminase activity (found in approximately 85% of patients), macrocytosis, and an
elevated fetal hemoglobin are supportive but not diagnostic of DBA. Congenital
anomalies including thumb malformations and various others are seen in 50% of DBA
patients, and, in turn, half of these are craniofacial abnormalities40.
Approximately 45% of DBA cases are familial41. The first DBA gene, mutated in about
25% of patients, was cloned and identified as RPS19, which encodes a protein component
of the 40S ribosomal subunit3,42. Patients are generally heterozygous with respect to
RPS19 mutations indicating that the disease likely results from protein
haploinsufficiency43. Studies of the yeast ortholog of RPS19 indicate it is required for
the maturation of 40S ribosomal subunits6 (Fig. 2). Yeast cells deficient in RPS19 have a
reduction in the steady-state level of 40S ribosomal subunits and compromised protein
synthetic capacity. Pre-40S particles that accumulate in cells depleted of RPS19 are
retained in the nucleolus and fail to recruit factors needed for rRNA processing and
transport to the cytoplasm.
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If human RPS19, like its yeast ortholog, is required for the maturation of 40S ribosomal
subunits, questions remain as to how haploinsufficiency for an essential ribosomal
protein results in the predominantly hematopoietic manifestations of the disease. Massey
and Ellis44 have proposed that differences in the level of individual ribosomal
components can make proteins limiting for ribosome assembly in some tissues and not
others, when present in a haploinsufficient state. As discussed later in this Perspective,
this may explain the tissue specificity characterizing disorders such as DBA. Recent
studies by other investigators showing that RPS19 interacts with the oncoprotein Pim1
have raised an alternative hypothesis, in which RPS19 links signal transduction pathways
with the translational machinery45. Finally, the observation that crosslinked dimers of
RPS19 function as agonists and antagonists of the C5a complement receptors7 suggests
other extraribosomal functions for RPS19 that may contribute to DBA pathophysiology
in a manner not currently understood.
As the different functions for RPS19 are gradually clarified, ongoing efforts to genotype
DBA patients and correlate clinical phenotypes with RPS19 mutations may assist in
distinguishing between these alternative hypotheses. Likewise, identifying other genes
responsible for DBA other than RPS19 will be critical in directing further research, as
well as in either validation or questioning of the ribosome and marrow failure link.
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SBDS and Shwachman-Diamond Syndrome: New Player on the Block
Shwachman Diamond syndrome (SDS), first described in 1964, is an autosomal recessive
disorder characterized by neutropenia, exocrine pancreatic insufficiency, and
metaphyseal dysostosis46,47. Neutropenia, found in 88-100% of patients, is the
hematologic hallmark of SDS, and in some patients there is also a defect in neutrophil
chemotaxis (reviewed in 48). Pancytopenia occurs in 10-65% of cases and may precede
progressive bone marrow dysfunction characterized by severe aplastic anemia,
myelodysplastic syndrome or acute leukemia, usually of myeloid origin49.
Most cases of SDS are caused by mutations in the SBDS gene4. While SBDS is highly
conserved in species as divergent as archaebacteria, little is known regarding the precise
function of its gene product. The localization of the archael SBDS in an operon with
subunits of the exosome, a complex of nucleases involved in a number of different RNA
processing reactions, initially hinted at a role for SBDS in RNA metabolism. These data
are supported by studies in yeast, showing that depletion of the SBDS ortholog, SDO1
(also known as YLR022c), interferes with the processing of the 35S rRNA primary
transcript8,9,50. In the initial screening experiments, which involved a panoramic view of
yeast mutants involved in RNA metabolism using regulated promoter alleles to silence
expression of selected genes, the SDO1 mutants exhibited a so-called processome-like
phenotype50. This is characterized by inefficient cleavage of the primary rRNA transcript
within the 5K-ETS and ITS1 sites, which in turn should lead to a defect in 40S subunit
maturation, similar to that seen with defects in RPS19 (Fig. 2). Although our own
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preliminary experiments confirm inefficient cleavage of the primary rRNA transcript51,
the exact molecular function of the SBDS orthologs is likely to be more complex than
initially believed and involve the 60S ribosomal subunit as well. In this regard, tagged
SDO1 co-purified with over 20 proteins involved in ribosome biosynthesis, including
components of the 60S subunit8. The finding that the human SBDS protein is localized to
the nucleolus further supports a role for this protein in ribosome synthesis52. More
detailed studies on the function of SBDS will be necessary to clarify this specific
function. As noted above for the genes involved in other bone marrow failure
syndromes, it would not be surprising to find extraribosomal functions for SBDS as well.
Treacher Collins Syndrome: Severing the Ribosome Synthesis/Bone Marrow
Failure Link?
Treacher Collins syndrome (TCS), an autosomal dominant disorder of craniofacial
development, is caused by mutations in the TCOF1 gene, which encodes a nucleolar
phosphoprotein called treacle (Table 1). Treacle has been shown to affect ribosomal
DNA transcription by interacting with upstream binding factor, an RNA polymerase I
transcription factor53 (Figs. 1 and 2). In addition, treacle plays a role in pre-rRNA
methylation54. Haploinsufficiency of treacle in TCS disrupts ribosome synthesis in a
manner reminiscent of that observed in dyskerin mutants, which also affect rRNA
modification. Yet, TCOF1 mutants lead to abnormal proliferation and/or differentiation
of neural crest precursor cells involved in craniofacial development without interfering
with hematopoiesis. A subset of DBA patients, who as a group appear to lack RPS19
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mutations, presents with craniofacial abnormalities indistinguishable from those seen in
TCS55,56. Thus, mutations in as yet unidentified DBA genes may give rise to ribosomal
defects reminiscent of TCOF1 haploinsufficiency, manifesting during embryogenesis and
again during erythroid development.
These results, together with the foregoing discussion, suggest that defects in factors
involved in ribosome synthesis affect tissues in different, highly specific ways that are
difficult to predict. Clearly, many questions remain unanswered regarding the bone
marrow failure - ribosome synthesis link. It will be important to determine if the
consequences of disrupting the function of ribosome synthesis factors result from
quantitative changes in protein synthetic capacity in a tissue-specific manner or instead a
differential sensitivity of certain cell lineages to a general reduction in protein synthetic
capacity. Only further experiments will be able to resolve these critical issues.
Defects in Ribosome Synthesis: The Cancer Connection
Mutations in genes involved in each of the diseases discussed above have the potential to
perturb the synthesis of ribosomal subunits and as such, fundamentally alter the protein
synthetic capacity of cells. Such alterations may also sensitize cells to apoptotic stimuli,
accelerating programmed cell death pathways. Recent evidence suggests that cytopenias
in many, if not all, of the bone marrow failure syndromes may be a consequence of
accelerated apoptotic death of hematopoietic progenitor cells (see references 57-64). A
possible explanation for this apoptotic sensitivity relates to the activation of the p53
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tumor suppressor. It has been postulated that disturbances in ribosome synthesis must be
detected and coupled with cell cycle arrest in order to prevent aberrant cell divisions.
Hence, close coordination exists between p53-mediated cell growth regulation and
cellular responses to malfunction of ribosome synthesis. Normally, ribosomal biogenesis
is coordinated by growth signals65. The tumor suppressors p53 (references 66,67), the RB
retinoblastoma protein68-70, and p19ARF (reference 71), have all been shown to interfere
with rRNA synthesis or processing, thereby controlling ribosomal biogenesis.
Overproduction of these tumor suppressors inhibits protein synthesis while arresting cell
growth in response to stress signals. Apparently, p53 can also sense perturbations in
ribosomal biogenesis, as from defects in rRNA synthesis and processing or disruption of
ribosome assembly72,73. Therefore, disruption of ribosomal biogenesis (and resulting
“nucleolar stress”13) should lead to p53 activation and oppose oncogenic
transformation74-76. While this may contribute to the proliferative defects in bone marrow
failure, how might leukemia or non-hematopoietic cancer evolve? Presumably, for
leukemia, there is strong selective pressure for clonal outgrowth of cells with mutations
that can compensate for the “ribosome-depleted” state. One way to increase ribosome
synthesis would be to overexpress the Myc oncoprotein77, a major regulator of ribosomerelated genes, or to inactivate RB, which dampens RNA polymerase I. For nonhematopoietic cancers as are seen in DBA78, mutations in ribosomal genes may be
directly oncogenic as suggested by the recent finding that heterozygous mutations in
several zebrafish ribosomal protein genes induce tumors79.
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Concluding Remarks
In this Perspective, we have attempted to critically appraise the hypothesis that defects in
ribosomal biogenesis underlie bone marrow failure. At present, the ribosome/marrow
failure association does not seem to rise to the level of a molecular paradigm. Treacher
Collins syndrome and anauxetic dysplasia demonstrate that defects in ribosome synthesis
can cause clinical syndromes that do not include bone marrow failure. Moreover, the
pathology observed in X-linked DC and CHH appear to be predominantly consequences
of extraribosomal functions of each affected gene product. In these latter examples,
however, associated defects in ribosome synthesis may serve as important disease
modifiers (Fig. 1). In this context, defects in ribosome synthesis may enhance disease
severity by compounding the effects mediated through the extraribosomal functions or by
expanding the range of clinical manifestations by affecting additional tissue types. These
data also do not exclude defects in ribosome synthesis as a primary cause for other bone
marrow failure syndromes such as DBA and SDS. Regardless of whether factors that
affect ribosome synthesis are a principal determinant or a modifier of disease severity in
the bone marrow failure syndromes, novel therapeutic strategies aimed at restoring
ribosomal function in hematopoietic cells may prove useful in treating cytopenias.
Finally, components of the ribosomal pathway may represent targets for cancer treatment,
which may break the vicious cycle between marrow failure and cancer predisposition.
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ACKNOWLEDGEMENTS
We thank Drs. Jeffrey Lipton and Amy Massey for critically reviewing the manuscript.
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25
Table 1. Genetic disorders linked to molecular defects in ribosomal
biogenesis.
Of this group, only Treacher Collins syndrome is not associated with bone
marrow failure.
Disease
X-linked dyskeratosis
congenita
Gene Defect
DKC1
Cartilage-hair hypoplasia
RMRP
Diamond-Blackfan
anemia
Shwachman-Diamond
syndrome
RPS19
Treacher Collins
syndrome
TCOF1
SBDS
Clinical Features
Abnormal skin pigmentation, nail
dystrophy, bone marrow failure,
cancer, others
Skeletal defects and short stature,
hypoplastic anemia, lymphoma,
others
Bone marrow failure, craniofacial
abnormalities, cancer, others
Bone marrow failure, pancreatic
insufficiency, short stature,
leukemia, others
Craniofacial abnormalities
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26
FIGURE LEGENDS
Fig. 1. Schematic relationship between ribosome synthesis and ShwachmanDiamond syndrome (SDS), Diamond-Blackfan anemia (DBA), Treacher Collins
syndrome (TCS), cartilage-hair hypoplasia (CHH), anauxetic dysplasia (AD), and
dyskeratosis congenita (DC). TCS is depicted by dotted lines, as it does not cause bone
marrow failure. Putative functions in ribosomal biogenesis attributed to each gene
product include: 40S ribosomal subunit maturation, RNA polymerase I (pol I)
transcription, rRNA methylation, rRNA cleavage, and pseudouridiylation (pseudo-U) of
rRNA. See text for details.
Fig. 2. Putative biochemical function for DKC1, TCOF1, SBDS, RPS19, and RMRP
in ribosomal biogenesis. For simplicity, the mammalian rRNA processing pathway is
depicted, whereas the putative function of each gene product is deduced from data
obtained from yeast and human orthologs. In the mammalian rRNA processing pathway,
cleavages at the external transcribed sequence (5’ETS) and internal transcribed sequences
(ITS1 and ITS2) lead to maturation of 18S, 5.8S, and 28S rRNA species. The 18S rRNA
is a component of the 40S ribosomal subunit. The 5.8S and 28S rRNAs, together with
the 5S rRNA (not shown), are components of the 60S ribosomal subunit. 40S and 60S
subunits are assembled into 80S ribosomes.
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27
Fig. 1.
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28
Fig. 2.
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Prepublished online February 28, 2006;
doi:10.1182/blood-2005-12-4831
Ribosomes and marrow failure: coincidental association or molecular
paradigm?
Johnson M Liu and Steven R Ellis
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