Functional diversity of large ribosomal protein 27 and small ribosomal protein 19 paralogs - 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.
