Tumor formation and inactivation of RIZ1, an Rb-binding member of a nuclear protein-methyltransferase superfamily

The retinoblastoma protein-interacting zinc finger gene RIZ (PRDM2) is a me mber, by sequence homology, of a nuclear protein-methyltransferase (MTase) superfamily involved in chromatin-mediated gene expression. The gene produc es two protein products, RIZ1 that contains a conserved MTase domain and RI Z2 that lacks the domain. RIZ1 gene expression is frequently silenced in hu man cancers, and the gene is also a common target of frameshift mutation in microsatellite-unstable cancers. We now report studies of mice with a targ eted mutation in the RIZ1 locus. The mutation inactivates RIZ1 but not RIZ2 . These RIZ1 mutant mice were viable and fertile but showed a high incidenc e of diffuse large B-cell lymphomas (DLBL) and a broad spectrum of unusual tumors. RIZ1 deficiency also accelerated tumorigenesis in p53 heterozygous mutant mice. Finally, several missense mutations of RIZ1 were found in huma n tumor tissues and cell lines; one of these was particularly common in hum an DLBL tumors. These missense mutations, as well as the previously describ ed frameshift mutation, all mapped to the MTase functional domains. All abo lished the capacity of RIZ1 to enhance estrogen receptor activation of tran scription. These data suggest a direct link between tumor formation and the MTase domain of RIZ1 and describe for the first time a tumor susceptibilit y gene among methyltransferases.