RESUMO
The atypical Rio1 protein kinases/ATPases, which exist in most archaea and eukaryotes, have been studied intensely to understand how they promote small ribosomal subunit (SSU) maturation. However, mutant and knockdown phenotypes in various organisms suggested roles in activities beyond SSU biogenesis, including the regulation of cell cycle progression (DNA transcription, replication, condensation, and segregation), cell division, metabolism, physiology, and development. Recent work with budding yeast, indeed, revealed that Rio1 (RIOK1 in metazoans) manages a large signaling network at the protein and gene levels via which it stimulates or restricts growth and division in response to nutrient availability. We examine how these findings translate to human cells and suggest that RIOK1 over-expression or mutations, as observed in primary cancer cells, may cause a mis-regulation of its network, contributing to cancer initiation and progression. We also reflect on how targeting RIOK1 might eradicate hitherto incurable tumors in the clinic.
Assuntos
Antígenos de Neoplasias/genética , Antígenos de Neoplasias/metabolismo , Animais , Antígenos de Neoplasias/química , Evolução Biológica , Divisão Celular , Proliferação de Células , Regulação da Expressão Gênica , Instabilidade Genômica , Humanos , Família Multigênica , Ligação Proteica , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismoRESUMO
Kinetochores assemble on centromeres via histone H3 variant CENP-A and low levels of centromere transcripts (cenRNAs). The latter are ensured by the downregulation of RNA polymerase II (RNAPII) activity, and cenRNA turnover by the nuclear exosome. Using S. cerevisiae, we now add protein kinase Rio1 to this scheme. Yeast cenRNAs are produced either as short (median lengths of 231 nt) or long (4458 nt) transcripts, in a 1:1 ratio. Rio1 limits their production by reducing RNAPII accessibility and promotes cenRNA degradation by the 5'-3'exoribonuclease Rat1. Rio1 similarly curtails the concentrations of noncoding pericenRNAs. These exist as short transcripts (225 nt) at levels that are minimally two orders of magnitude higher than the cenRNAs. In yeast depleted of Rio1, cen- and pericenRNAs accumulate, CEN nucleosomes and kinetochores misform, causing chromosome instability. The latter phenotypes are also observed with human cells lacking orthologue RioK1, suggesting that CEN regulation by Rio1/RioK1 is evolutionary conserved.