The duality of PRDM proteins: epigenetic and structural perspectives
2022
Di Tullio, Federico | Schwarz, Megan | Zorgati, Habiba | Mzoughi, Slim | Guccione, Ernesto
PRDF1 and RIZ1 homology domain containing (PRDMs) are a subfamily of Krüppel‐like zinc finger proteins controlling key processes in metazoan development and in cancer. PRDMs exhibit unique dualities: (a) PR domain/ZNF arrays—their structure combines a SET‐like domain known as a PR domain, typically found in methyltransferases, with a variable array of C2H2 zinc fingers (ZNF) characteristic of DNA‐binding transcription factors; (b) transcriptional activators/repressors—their physiological function is context‐ and cell‐dependent; mechanistically, some PRDMs have a PKMT activity and directly catalyze histone lysine methylation, while others are rather pseudomethyltransferases and act by recruiting transcriptional cofactors; (c) oncogenes/tumor suppressors—their pathological function depends on the specific PRDM isoform expressed during tumorigenesis. This duality is well known as the ‘Yin and Yang’ of PRDMs and involves a complex regulation of alternative splicing or alternative promoter usage, to generate full‐length or PR‐deficient isoforms with opposing functions in cancer. In conclusion, once their dualities are fully appreciated, PRDMs represent a promising class of targets in oncology by virtue of their widespread upregulation across multiple tumor types and their somatic dispensability, conferring a broad therapeutic window and limited toxic side effects. The recent discovery of a first‐in‐class compound able to inhibit PRDM9 activity has paved the way for the identification of further small molecular inhibitors able to counteract PRDM oncogenic activity.
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