Friday, November 22, 2024
11/22/2024
Project Summary Diamond-Blackfan anemia (DBA) is a rare hemorrhagic disease in which the bone marrow cannot make enough red blood cells, possibly due to issues with ribosomes, the translation machinery essential for protein synthesis. Studying ribosome gene expression will enhance understanding of DBA, often noticeable in the first year of life, and find better treatments for young patients. While ribosomes maintain a consistent primary structure and function across various life forms, they exhibit notable heterogeneity due to variations in ribosomal rRNA and protein content. This diversity is accentuated in organisms by the presence of numerous paralogous ribosomal proteins scattered throughout their genomes. Mutations in these paralogs result in distinct phenotypes, potentially due to the integration of different ribosomal proteins affecting mRNA translation specificity. This suggests a broader regulatory role for ribosomes in protein synthesis beyond traditional transcriptional mechanisms. However, the unique phenotypes observed in paralog mutants could result from generating abnormal or different amounts of ribosomes rather than truly specialized functions of heterogeneous ribosomes. This proposed study aims to clarify this ambiguity by investigating the functional divergence of two critical ribosomal proteins in Schizosaccharomyces pombe (S. pombe): the large subunit protein 27 (Rpl27) and the small subunit protein 19 (Rps19). These proteins, encoded by distinct paralog genes, exhibit differential expression and regulatory mechanisms. Our preliminary results show that the absence of Rpl27 paralogs leads to unique cellular phenotypes, characterized by asymmetric expression and varying mRNA and protein levels under both normal and stress conditions. Similarly, Rps19 paralogs, despite sharing 97% protein sequence identity, display divergent regulatory elements and expression patterns, particularly under heat stress. Our study is designed to test the hypothesis that differences in cellular phenotype resulting from the absence of ribosomal protein paralogs are due to variations in protein sequence, abundance, mRNA specificity, or differential functionality under stress. This investigation, focusing on Rpl27 and Rps19 paralogs, has the potential to transform our understanding of ribosomal biology and uncover new regulatory mechanisms in the expression of ribosomal protein paralog genes, which may pave the way for new treatments for conditions like DBA and improve childcare.
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