Ribosomopathies: Many Questions and A Few Answers- Juniper Publishers
Juniper Publishers- Journal of cell Science
Abstract
The ribosomopathies are a diverse group of disorders
that are caused by mutations in a gene encoding either a ribosomal
protein, or a component of the apparatus required for ribosome
biosynthesis. The dysfunction of RPs has been linked to the development
and progression of hematological, metabolic, and cardiovascular diseases
and cancer. Ribosome biogenesis appears to be an attractive target for
cancer prevention or therapy
Abbreviation: rRNA: ribosomal
RNA; RPs: Ribosomal Proteins; snoRNAs: small nucleolar RNAs; T-ALL:
T-cell Acute Lymphoblastic Leukemia; MDM2: Murine Double Minute-2; GBM:
Glioblastoma MultiformeIntroduction
Structure and function of ribosomes
Ribosomes are essential components of the protein
synthesis machinery [1]. Ribosomes are large complex molecules [2]
comprised of ribosomal RNA (rRNA), ribosomal proteins (RPs), and small
nucleolar RNAs (snoRNAs) [3]. rRNA catalyzes peptide bond formation
during protein synthesis; RPs optimize rRNA processing and stabilize the
ribosome’s final structure; and snoRNAs primarily regulate chemical
modifications of other RNAs [3]. RNA and protein are assembled into a
functional, multi-subunit enzyme [2]. Ribosomes are universally
responsible for the quality and quantity of proteins in all cells [4].
RPs has extra-ribosomal functions that are involved in cell
proliferation, differentiation, apoptosis, DNA repair, and other
cellular processes. A subset of RPs also acts as “watch guards” to
detect the defects in ribosome biogenesis (the synthesis of the
ribosome) [1].
Ribosomal stress
The TP53, mTOR, and MYC pathways are evidently each
important for ribosome biogenesis. It has become apparent, that these
pathways interact and influence each other [2]. Disruption of ribosome
biogenesis results in ribosomal stress which triggers activation of the
p53 signaling pathway, through RPs–MDM2 interactions, resulting in
p53-dependent cell cycle arrest and apoptosis. RPs also regulates
cellular functions through p53-independent mechanisms [1]. Under stress
situations, ribosome activity decreased, protein synthesis is reduced,
with subsequent growth arrest [1].
The ribosomopathies
These are a diverse group of disorders that is caused
by mutations in a gene encoding either a ribosomal protein, or a
component of the apparatus required for ribosome biosynthesis [2].
Clinical features of the ribosomopathies can include bone marrow
failure, developmental abnormalities, and increased risk of cancer [3].
Immune defects have also been proposed to be a hallmark [2]. However,
Ribosome biogenesis disorders are highly heterogeneous in their physical
manifestations [2]. Ribosomal dysfunction can cause a wide range of
presentation and severities that differ dramatically even among patients
with the same diagnosis [3]. Despite their heterogeneity at a clinical
level and modes of inheritance, they affect the same biochemical process
[2].
Among the autosomal dominant ribosomopathies are
Diamond–Black fan Anemia (DBA); Treacher Collins syndrome which also has
an autosomal recessive form; isolated congenital asplenia; and the
autosomal dominant form of aplasia cutis congenita. The ribosomopathies
inherited in an autosomal recessive fashion include Shwachman–Diamond
syndrome [2].
Some ribosomopathies specifically affect the
craniofacial skeleton (i.e. Treacher Collins Syndrome), while other
ribosomopathies encompass combinatorial malformations of the
craniofacial, axial and/or limb skeletal systems (DBA, Postaxial a
acrofacial dysostosis, Roberts syndrome, Schwachman-Diamond syndrome,
Cartilage Hair hypoplasia and Bowen-Conradi syndrome). Bone marrow
failure may or may not be present as part of the clinical spectrum of
skeletal anomalies. Bone marrow
failure is a defining feature of DBA, Shwachman-Diamond
syndrome and Cartilage Hair Hypoplasia but is not a recognized
component of Treacher Collins syndrome or Postacrofacial
dysostosis [4].
The specific mechanism underlying the ribosomopathies
Although the specific mechanism underlying the
ribosomopathies is frequently unclear, the generally accepted
etiology is that processing delays or defects in rRNA maturation
result in an imbalance of mature ribosomes, leading to reduced
rates of protein synthesis and cell proliferation [2]. Individually,
the ribosomopathies are rare, phenotypically unique [2]. There
is a surprising tendency toward tissue specificity in these
diseases [2]. Several different mechanisms have been proposed
to underlie the observed clinical differences and variability [4]
and the tissue specificity of ribosome biogenesis disorders. This
includes in part the emerging concept of “specialized ribosomes,”
in which tissue-specific variations in ribosomal structure or
function confer regulatory specificity in translation [3]. It is also
possible, and perhaps even more likely, that ribosome biogenesis
is spatiotemporally dynamic, and different threshold levels of
activity may be required in one tissue versus another at different
times, in order to affect normal development [4].
How mutations in genes critical for ribosome
biogenesis, which might normally have global or
widespread roles during organism development, can
lead to such selective traits?
The types of alterations in gene function, together with the
magnitude of their effect on ribosome biogenesis in specific
tissues at specific developmental times may play a role [4].
Another possible mechanism that may account for some of
the clinical differences is how each specific mutation affects
the function of the gene product [4], the selective translation
of specific mRNAs directed by the ribosome, extra-ribosomal
functions of ribosomal proteins and ribosomal biogenesis
factors, and differential requirements for ribosomes in different
tissues [2]. Other factors include the discovery of ribosomal
protein variants that may influence the absolute transcriptional
levels and or possible isoforms of rDNA transcription [4]. In
addition to, the diverse roles played by regulatory pathways in
modulating ribosome biogenesis disorders [2]. The individual
contributions of TP53, mTOR, and MYC pathways to tissuespecific
effects in ribosomopathies are unclear [2].
The composition of ribosomes and other elements of the
translational apparatus can also vary within cells, especially in
neurons, where certain RPs and RNAs are selectively enriched
in axons or dendrites relative to the soma. These variations in
turn affect the translation of specific subsets of mRNAs and are
clinically significant in several ribosomopathies [3].
The ribosomopathies and cancer
An aberration or deregulation in any of ribosome biogenesis
processes may drive malignant transformation and lead to an
abnormal cellular phenotype [1]. Somatic mutations in genes
encoding RPs seem to be a common feature of many cancers,
suggesting their importance in oncogenesis [5].
Hematologic malignancies
Several hematologic malignancy–associated RP mutations
have been identified. RPS14 haploinsufficiency is the
predominant cause of erythroid hypoplasia in 5q– syndrome.
Mutation of RPL22 has been identified in T-ALL patients. Somatic
RP gene mutations and deletions in RPL5, RPL10, and RPL22
were found in 20% of acute T-ALL children. Less frequently,
defects in RPL11 were found. RPS15 mutations were noted
exclusively in the more aggressive forms of CLL [5]. About 25% of
DBA patients harbor a mutation in the RPS19 gene; another 20%
carry mutations in other ribosomal protein genes. DBA patients
have a modest risk of developing leukemias, the myelodysplastic
syndromes, and other cancers [6].
Solid tumors
RPL5 has been found to be mutated in GBM and other tumors.
Other identified RP mutated genes were: RPL5 in cutaneous
melanoma and GBM, RPL11 in cutaneous melanoma, RPS5 in
gastric adenocarcinoma, RPS20 in uterine corpus endometrial
carcinoma, and RPSA in gastric adenocarcinoma [5].
Future direction
The differential expression of RPs in several cancer types
makes them attractive candidates that may serve as noninvasive
biomarkers for cancer. Ribosome biogenesis appears to be an
attractive target for cancer prevention or therapy [1].
Conclusion
Influencing RP expression may emerge as an important
therapeutic target strategy in the future.
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