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Chem Bio Seminar-Prof. Sarah Slavoff, Yale University
October 5, 2021 @ 3:30 pm - 4:30 pm
“Dark Matter of the Human Genome”
Advanced methods in next-generation sequencing and proteogenomics have revealed thousands of previously invisible human genes. This previously unannotated “dark matter” of the human genome includes small open reading frames (smORFs) encoding polypeptides of fewer than 100 amino acids, and alternative open reading frames (alt-ORFs) encoding proteins 100 amino acids or larger. SmORFs previously escaped detection due to their short lengths, overlap with annotated protein coding sequences in different reading frames, and/or initiation with non-AUG start codons. Recent studies have shown that hundreds of smORFs are required for cell growth and survival, and some smORF-encoded polypeptides or “microproteins” bind to and regulate the activity of macromolecular complexes involved in critical cellular processes and disease. However, the vast majority of smORFs remain entirely uncharacterized. My research group is developing advanced mass spectrometry proteomics-based approaches to accelerate the importance process of smORF functional chracterization, and in this presentation, I will describe several novel microproteins involved in essential cellular processes and the (chemo)proteomic technologies utilized to discover them. Taken together, our findings demonstrate that interfacing phosphoproteomics, interactomics and chemoproteomics with proteogenomics can drive forward our understanding of the (patho)physiological functions of recently discovered smORF-encoded polypeptides and microproteins.