RNA-Protein interactions regulating mRNA stability

Project Details

Description

DESCRIPTION (provided by applicant): Globin gene expression is maintained and
accentuated as a consequence of the unusual stability of the globin mRNAs
during differentiation into a transcriptionally silent enucleated erythrocyte.
Relatively little is known about the components that regulate globin mRNA
stability. Irregularities in mRNA stability can have profound consequences that
manifest as clinical phenotypes including thalassemias as exemplified by the
athalassemia, a Constant Spring (a). Patients with the a S variant are severely
anemic with virtually no mRNA in circulating reticulocytes due to a mutation
that causes instability of the aCS mRNA. However, the molecular mechanisms
involved in specific turnover of mRNAs are poorly understood and very few
nucleases involved in the degradation of mRNA have been identified. We have
devised an in vitro mRNA decay assay which recapitulates regulated mRNA
turnover of the a-globin mRNA and have identified a sequence specific
endoribonuclease, ErEN, which is involved in the degradation of this mRNA. ErEN
is an erythroid specific endoribonuclease which specifically cleaves the
a-globin mRNA both in vitro and in cells thereby demonstrating that this
nuclease activity is essential for the normal biogenesis of a-globin mRNA. The
long term objective of this proposal is to understand the determinants that
regulate globin mRNA stability and decay. The focus of this proposal is: (AIM
1) to biochemically isolate and molecularly clone ErEN; (AIM 2) to functionally
characterize the endoribonuclease activity and its expression profile in
erythropoiesis; (AIM 3) to initiate targeted regulation of heterologous mRNA
and (AIM 4) to identify additional erythroid mRNAs regulated by ErEN. A
thorough understanding of all the molecular controls of globin gene expression
are necessary to efficiently ameliorate hemoglobinopathies and human genetic
disorders in general. This work will provide fundamental insights into mRNA
turnover, which is an important yet relatively unexplored component of gene
expression, and afford novel approaches to regulate gene expression in
therapeutic strategies.
StatusFinished
Effective start/end date5/1/972/28/08

Funding

  • National Institute of Diabetes and Digestive and Kidney Diseases: $296,120.00
  • National Institute of Diabetes and Digestive and Kidney Diseases: $292,204.00
  • National Institute of Diabetes and Digestive and Kidney Diseases
  • National Institute of Diabetes and Digestive and Kidney Diseases: $291,593.00
  • National Institute of Diabetes and Digestive and Kidney Diseases: $148,200.00
  • National Institute of Diabetes and Digestive and Kidney Diseases: $148,200.00
  • National Institute of Diabetes and Digestive and Kidney Diseases
  • National Institute of Diabetes and Digestive and Kidney Diseases: $298,122.00
  • National Institute of Diabetes and Digestive and Kidney Diseases: $300,320.00
  • National Institute of Diabetes and Digestive and Kidney Diseases

ASJC

  • Genetics
  • Molecular Biology
  • Cell Biology

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