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Translational recoding in human disease
Author(s) -
Advani Vivek M,
Kobylarz Ryan C,
Dinman Jonathan D.
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.1065.1
Subject(s) - biology , gene , genetics , translation (biology) , computational biology , translational efficiency , gene expression , dyskeratosis congenita , translational regulation , genome , messenger rna , telomere
Translational recoding is emerging as an important post‐transcriptional regulatory mechanism. Prior studies from our laboratory have explored how Programmed −1 Ribosomal Frameshifting (−1 PRF) fits within this paradigm. Computational analysis predicts ~10% of the genes in humans have at least one functional −1 PRF signal which translates to 1,943 high probability candidates in the human genome. Analysis of predicted −1 PRF signals across 20 genomes suggests that it is a universal molecular mechanism1, and demonstrate that >99% of such events function as mRNA destabilizing elements through at least two pathways2,3. In published work we have explored the biological significance of the connection between −1 PRF and NMD on telomere maintenance in yeast4 and the immune response in humans5. Here, we are exploring how abnormalities in ribosome function are implicated in both congenital and acquired syndromes, broadly classified as ‘ribosomopathies’, contribute to disease pathogenesis. Preliminary findings using yeast and human cell‐based models for X‐linked Dyskeratosis Congenita (X‐DC), Spinocerebellar ataxia 26 family (SCA26) and Diamond‐Blackfan anemia (DBA) as models suggest that these genetically inherited defects are caused by translational fidelity defects, with attendant effects on mRNA abundance and gene expression. The observations that global dysregulation of −1 PRF has deleterious effects on gene expression leads us to hypothesize that −1 PRF plays an important role in regulating cellular gene expression. Through the First‐year Innovative and Research Experiences (FIRE) ‐ Found in Translation (FIT) Undergraduate Research Program at the University of Maryland, we have validated functional −1 PRF signals in over 40 human genes, involved in processes including immune signaling, translation initiation, cancer, anemias and other diseases. This study will increase our understanding of how defects in the interplay between mRNA and ribosomes contribute to human disease. Support or Funding Information NIH R01 HL119439, NIH R01 GM117177