Expanding Proteome Diversity Through Alternate RNA Decoding
BioE Professor Nikolai Slavov’s laboratory published research on “Alternate RNA decoding results in stable and abundant proteins in mammals” in Nature. Since the 1960s, the genetic code has been used to predict protein sequences from DNA and mRNA sequences. Slavov’s article demonstrates that these predictions miss thousands of protein sequences present in human tissues.
Across >1,000 human samples, we identified numerous abundant proteins whose amino acid sequences differ from those predicted by the genetic code.
These proteins are not rare translation byproducts. They accumulate to thousands of copies per cell. Some are more abundant than the proteins predicted by the genetic code from the same transcripts.
Their abundance reflects a combination of alternate RNA decoding mechanisms — including codon-anticodon mismatches, tRNA abundance, and RNA modifications — and selective stabilization of the resulting proteins. The last factor – protein stability – emerges as a major determinant of protein abundance across proteins, proteoforms, and cell types: https://slavovlab.net/research.htm#Proteostasis
Alternate RNA decoding is pervasive across functional groups of proteins, healthy and diseased tissues. It affects proteins playing key roles in neurodegeneration, and some alternately decoded proteins show strong enrichment in tumors compared to their surrounding tissues.
The findings reveal a layer of proteome diversity that is largely invisible to DNA and RNA sequences alone. Our knowledge of the proteome remains relatively limited: It is the next big Scientific Frontier.
This discovery has been a long and exhilarating journey with Shira Tsour and the Slavov Lab team. It started in 2019 and proceeded through many challenges and thrilling highs. A journey that has opened new perspectives that we long to explore!