Abnormalities in ribosome function that are implicated in both congenital and acquired bone marrow failure syndromes in humans are classified under the broad umbrella of ribosomopathies. A recent collaboration between our two laboratories has initiated a completely new avenue of research by establishing an evolutionarily conserved role for ribosome modifications mediated by the pseudouridine synthase dyskerin in specific aspects of translation control. The functional role of pseudouridine (?) modifications is of great medical importance as mutations in DKC1, the gene encoding for dyskerin, are found in a number of diseases including X-linked dyskeratosis congenita (X-DC), Hoyeraal-Hreidarsson syndrome, and numerous cancers. Importantly, our published work has identified that the decreased affinity of rRNA ? defective ribosomes for tRNAs results in increased rates of programmed -1 ribosomal frameshifting (-1 PRF), a molecular mechanism that is emerging as an important regulator of gene expression. This proposal seeks to test the hypothesis that global changes in -1 PRF affect the expression of specific subsets of mRNAs encoding key hematopoietic factors, that may contributing to some of the pathological features associated with X- DC. Support for this hypothesis is evident from our extensive published and unpublished findings showing that increased rates of -1 PRF promotes rapid degradation of specific mRNAs through the Nonsense-Mediated mRNA Decay (NMD) pathway. Furthermore, we have demonstrated that rRNA ? levels are impaired in hematopoietic cells from X-DC patients harboring distinct DKC1 mutations. Importantly, our preliminary and published data also suggest that one important functional class of mRNAs involved in telomere maintenance is regulated by this mechanism in both yeast and human cells and is disrupted in X-DC patients, thus linking rRNA ? defects and telomere shortening. By utilizing X-DC as a disease paradigm and combining three model systems, yeast, mouse and humans, in this proposal we will extend our novel findings and identify the repertoire of mRNAs that underlie bone marrow failure associated with ribosome dysfunction and determine the therapeutic potential of inhibiting NMD and -1 PRF in X-DC.
Aim 1 of this proposal seeks to identify the repertoire of mRNAs whose expression is affected by rRNA ? defects in yeast, mouse and human cells using two complementary approaches.
Aim 2 will determine the mechanisms through which impaired rRNA ? alters expression of -1 PRF containing mRNAs.
Aim 3 is oriented towards determining the therapeutic potential of targeting NMD and -1 PRF in X-DC. By the end of the proposed studies, we will have 1) established a new paradigm for understanding ribosomopathies, 2) identified specific genes that can be used as biomarkers and targeted for therapeutic intervention, and 3) explored novel approaches to treat this class of diseases.

Public Health Relevance

Abnormalities in ribosome function are implicated in both congenital and acquired bone marrow failure syndromes, often referred to as 'ribosomopathies'. Here we will test the hypothesis that dysregulation of programmed -1 ribosomal frame shifting affects the expression of specific subsets of genes and that when deregulated may contribute to disease pathogenesis. Identification, validation, and therapeutic rescue of genes affected by ribosome dysfunction will provide novel diagnostic and prognostic markers for bone marrow failure and identify a novel therapy for treatment of this class of diseases.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL119439-01A1
Application #
8761841
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Qasba, Pankaj
Project Start
2014-08-01
Project End
2018-04-30
Budget Start
2014-08-01
Budget End
2015-04-30
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Maryland College Park
Department
Anatomy/Cell Biology
Type
Earth Sciences/Resources
DUNS #
City
College Park
State
MD
Country
United States
Zip Code
20742
Girardi, T; Vereecke, S; Sulima, S O et al. (2017) The T-cell leukemia-associated ribosomal RPL10 R98S mutation enhances JAK-STAT signaling. Leukemia :
Sulima, Sergey O; Hofman, Isabel J F; De Keersmaecker, Kim et al. (2017) How Ribosomes Translate Cancer. Cancer Discov 7:1069-1087
Meydan, Sezen; Klepacki, Dorota; Karthikeyan, Subbulakshmi et al. (2017) Programmed Ribosomal Frameshifting Generates a Copper Transporter and a Copper Chaperone from the Same Gene. Mol Cell 65:207-219
Paolini, Nahuel A; Attwood, Martin; Sondalle, Samuel B et al. (2017) A Ribosomopathy Reveals Decoding Defective Ribosomes Driving Human Dysmorphism. Am J Hum Genet 100:506-522
Moomau, Christine; Musalgaonkar, Sharmishtha; Khan, Yousuf A et al. (2016) Structural and Functional Characterization of Programmed Ribosomal Frameshift Signals in West Nile Virus Strains Reveals High Structural Plasticity Among cis-Acting RNA Elements. J Biol Chem 291:15788-95
Kisly, Ivan; Gulay, Suna P; Mäeorg, Uno et al. (2016) The Functional Role of eL19 and eB12 Intersubunit Bridge in the Eukaryotic Ribosome. J Mol Biol 428:2203-16
Mailliot, Justine; Garreau de Loubresse, Nicolas; Yusupova, Gulnara et al. (2016) Crystal Structures of the uL3 Mutant Ribosome: Illustration of the Importance of Ribosomal Proteins for Translation Efficiency. J Mol Biol 428:2195-202
Advani, Vivek M; Dinman, Jonathan D (2016) Reprogramming the genetic code: The emerging role of ribosomal frameshifting in regulating cellular gene expression. Bioessays 38:21-6
Truitt, Morgan L; Ruggero, Davide (2016) New frontiers in translational control of the cancer genome. Nat Rev Cancer 16:288-304
Dinman, Jonathan D (2016) Pathways to Specialized Ribosomes: The Brussels Lecture. J Mol Biol 428:2186-94

Showing the most recent 10 out of 22 publications