An RNA recognition motif in Wilms' tumour protein (WT1) revealed by structural modelling

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Abstract
The Wilms' tumour suppressor gene 1 (WT1)1,2 encodes four C2H2 zinc finger-containing proteins3 critical for normal mammalian urogenital development4. Mutations in this gene are observed in the childhood kidney cancer, Wilms' tumour (WT)5. WT1 can bind specific DMA targets within the promoters of many genes6–9 and both transcriptional repression and activation domains have been identified10. On this basis, it has been assumed that regulation of transcription is the basis of WT1 tumour suppressor activity. However, subnuclear localization studies have revealed an association between WT1 proteins and ‘speckled bodies’ within the nucleus. Degradation of nuclear RNA in cells expressing WT1 abolishes this speckled localization and WT1 co-immunoprecipitates with a number of spliceosomal proteins, suggesting that it may also bind to RNA11. Using structural rather than sequence comparison, we have now identified an evolutionarily conserved N-terminal RNA recognition motif (RRM) in all known WT1 isoforms similar to that in the constitutive splicing factor U1A. Given the association between WT1 mutations and Wilms' tumours, this study, together with other recent findings, may suggest a novel tumour suppression mechanism.