Mis3 with a conserved RNA binding motif is essential for ribosome biogenesis and implicated in the start of cell growth and S phase checkpoint

Abstract

In normal somatic cell cycle, growth and cell cycle are properly coupled. Although CDK (cyclin-dependent kinase) activity is known to be essential for cell cycle control, the mechanism to ensure the coupling has been little understood. We here show that fission yeast Mis3, a novel evolutionarily highly conserved protein with the RNA-interacting KH motif, is essential for ribosome RNA processing, and implicated in initiating the cell growth. Growth arrest of mis3-224, a temperature sensitive mutant at the restrictive temperature, coincides with the early G2 block in the complete medium or the G1/S block in the release from nitrogen starvation, reflecting coupling of cell growth and division. Genetic interactions indicated that Mis3 shares functions with cell cycle regulators and RNA processing proteins, and is under the control of Dsk1 kinase and PP1 phosphatase. Mis3 is needed for the formation of 18S ribosome RNA, and may hence direct the level of proteins required for the coupling. One such candidate is Mik1 kinase. mis3-224 is sensitive to hydroxyurea, and the level of Mik1 protein increases during replication checkpoint in a manner dependent upon the presence of Mis3 and Cds1. Mis3 is essential for ribosome biogenesis, supports S phase checkpoint, and is needed for the coupling between growth and cell cycle. Whether Mis3 interacts solely with ribosomal precursor RNA remains to be determined.