The global map of Rio1 activity in Saccharomyces cerevisiae

In Saccharomyces cerevisiae, the kinase Rio1 regulates rDNA transcription and segregation, pre-rRNA cleavage, and 40S ribosomal subunit maturation. Other roles are unknown. Human orthologue RIOK1; which is frequently overexpressed in malignancies, drives tumor growth and metastasis. Again, also RIOK1 biology is poorly understood. In this study, we charted the global activity of Rio1 in budding yeast. By producing and systems-integrating its protein-interaction, gene-transcription, and chromatin-binding maps we generated Rio1's multi-layered activity network, which controls protein synthesis and turnover, metabolism, growth, proliferation, and genetic stability. Rio1 regulates itself at the transcriptional level, and manages its network both directly and indirectly, via a battery of regulators and transcription factors, including Gcn4. We experimentally confirmed the network and show that Rio1 commands its downstream circuit depending on the growth conditions encountered. We also find that Rio1 and RIOK1 activities are functionally equivalent. Our data suggest that pathological RIOK1 expression may deregulate its network and fuel promiscuous transcription and ribosome production, uncontrolled metabolism, growth, proliferation, and chromosomal instability; well-known contributors to cancer initiation, maintenance and metastasis.在酿酒酵母（Saccharomyces cerevisiae）中，Rio1激酶可调控核糖体DNA（rDNA）转录与分离、核糖体前体RNA（pre-rRNA）剪切以及40S核糖体亚基（40S ribosomal subunit）成熟，其余功能尚未明确。其人类同源基因（human orthologue）RIOK1在多种恶性肿瘤中常呈过表达状态，可驱动肿瘤生长与转移，但目前对于RIOK1的生物学功能仍知之甚少。本研究对酿酒酵母内Rio1的全局活性开展了系统解析：通过构建并整合其蛋白质相互作用、基因转录以及染色质结合图谱，我们构建了Rio1的多层活性调控网络，该网络可调控蛋白质合成与周转、代谢、生长、增殖以及遗传稳定性。Rio1可在转录水平实现自我调控，并通过包括Gcn4在内的一系列调控因子与转录因子，直接或间接调控该网络。我们通过实验验证了该调控网络，并证实Rio1可根据所处生长条件调控其下游通路。此外，本研究发现Rio1与RIOK1的活性功能等价。本研究数据提示，病理性RIOK1过表达可能会使其调控网络失调，进而引发异常转录、核糖体生成失控、代谢紊乱、异常增殖以及染色体不稳定性——上述均为已知的癌症发生、维持与转移的关键诱因。