Ribosomes are essential nanomachines responsible in all living cells for converting the information encoded in messenger RNAs to proteins. At the functional core of the ribosome is ribosomal RNA, a ribozyme that catalyzes the critical steps of decoding and amino acid polymerization.
“Cancer cells are addicted to ribosomes.” Cancer cells are more sensitive to treatment that inhibit translation or ribosome production because they rely on more abundant protein biosynthesis.
The Lafontaine Lab has characterized ribosome biogenesis and function for >20 years with a particular emphasis on RNA processing (how mature ribosomal RNAs are produced from polycistronic precursors) and RNA modification. Ribosome biogenesis is initiated in the nucleolus, a dynamic nuclear organelle whose morphology is a potent indicator of the health status of a cell. The size, shape, and number of nucleoli per cell vary greatly in normal and pathological situations such as viral infection and proliferative disease (cancer). Yet the nucleolus is not widely used by pathologists, for lack of reliable assays that might be used routinely in a clinical setting. The Lab has developed a powerful software for characterizing nucleolar disruption qualitatively and quantitatively with a precise numerical index: the index of nucleolar disruption or iNo score. As proof-of-concept, the team has depleted human cells expressing a fluorescent nucleolar reporter construct of each of the eighty ribosomal proteins, one by one, and systematically assessed nucleolar integrity. Unexpectedly, we found only a few ribosomal proteins to be required to maintain nucleolar integrity, the strongest contributors being uL5 and uL18. These are precisely the two factors which, together with the 5S rRNA, form a trimeric ribonucleoprotein complex important in regulating the homeostasis of the anticancer protein p53.
The Lab has also characterized the involvement of two small nucleolar RNAs, U3 and U8, in tumorigenesis, showing in a xenograft model that the suppression of their expression inhibits tumor formation. Finally, the lab has contributed to the characterization of melanoma-specific long non-coding RNA, Sammson, showing that the suppression of its expression kills even the more resistant melanoma cells.
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