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Isolation of a Mammalian Homologue of a Fission Yeast Differentiation Regulator

ABSTRACT In the fission yeast Schizosaccharomyces pombe thenrd1 + gene encoding an RNA binding protein negatively regulates the onset of differentiation. Its biological role is to block differentiation by repressing a subset of the Ste11-regulated genes essential for conjugation and meiosis until the cells reach a critical level of nutrient starvation. By using the phenotypic suppression of the S. pombetemperature-sensitive pat1 mutant that commits lethal haploid meiosis at the restrictive temperature, we have clonedROD1, a functional homologue ofnrd1 +, from rat and human cDNA libraries. Likenrd1 +, ROD1 encodes a protein with four repeats of typical RNA binding domains, though its amino acid homology to Nrd1 is limited. When expressed in the fission yeast,ROD1 behaves in a way that is functionally similar tonrd1 +, being able to repress Ste11-regulated genes and to inhibit conjugation upon overexpression. ROD1is predominantly expressed in hematopoietic cells or organs of adult and embryonic rat. Like nrd1 + for fission yeast differentiation, overexpressed ROD1 effectively blocks both 12-O-tetradecanoyl phorbol-13-acetate-induced megakaryocytic and sodium butyrate-induced erythroid differentiation of the K562 human leukemia cells without affecting their proliferative ability. These results suggest a role for ROD1 in differentiation control in mammalian cells. We discuss the possibility that a differentiation control system found in the fission yeast might well be conserved in more complex organisms, including mammals.