The duality of PRDM proteins: epigenetic and structural perspectives

Abstract

PRDMs are a subfamily of Kruppel-like zinc finger proteins controlling key processes in metazoan development and in cancer. PRDMs exhibit unique dualities: (i) PR domain/ZNF arraystheir 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; (ii) 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 co-factors; (iii) 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.

Cancer epigenetics: promises and pitfalls for cancer therapy

“…PR domain zinc finger proteins (PRDMs) are a protein family with key roles in gene expression regulation and chromatin architecture. Also in this issue, Slim Mzoughi and Ernesto Guccione review the dualities presented by PRDMs and explore how these dual roles affect oncogenesis [10]. In particular, the authors emphasise that, depending on which PRDM isoforms are expressed, they can act either as transcriptional activators or transcriptional repressors since the activity of some PRDMs directly catalyses histone lysine methylation, while that of others leads to the recruitment of transcriptional co‐factors.…”

“…Moreover, they highlight that different PRDM isoforms exert opposite effects on cancer progression, with some having a tumour‐suppressive role while others act as oncogenes. Additionally, the therapeutic potential of selective small molecules targeting specific PRDM isoforms is presented in this article [10].…”

Distinct developmental phenotypes result from mutation of Set8/KMT5A and histone H4 lysine 20 in Drosophila melanogaster

“…88 There are four PRDM proteins (Blimp-1, Hamlet, CG43347, Prdm13) in insect genomes whereas this family has expanded to nineteen proteins in humans. 29,48,88 In Drosophila, the protein encoded by PR-Set7/CG3307 is orthologous to the human H4K20 methyltransferase SETD8/KMT5A and it neither contains a PR domain nor any predicted zinc finger motifs 15,27,61 (Figure 1). In contrast, human PRDM7 (PR/SET Domain 7) is an H3K4 methyltransferase that is most closely related to the KRAB and Zn finger domain protein, PRDM9 10 (Figure 1).…”

PRDM12 in Health and Diseases

“…Moreover, as mentioned above, unlike the other PRDM family members, a unique transcript is known for PRDM12 gene signifying, which means that the well-known “Yin and Yang” mechanism cannot function [ 28 ]. Indeed, it is recognized that different isoforms exist for almost all PRDM family members, and they play opposite roles in cancer; this duality is termed the ‘Yin and Yang’ mechanism, typical of PRDMs and involving a complex regulation of alternative splicing or alternative promoter usage, to generate full-length or PR-lacking isoforms [ 1 , 26 , 27 , 28 ].…”

“…Most PRDM genes express two main molecular variants, with one lacking the PR domain. These two isoforms, which can be generated by either alternative splicing or the alternative use of different promoters, play opposite roles in cancer [ 1 , 25 , 26 ]. Specifically, the full-length product (PR-plus) usually acts as a tumor suppressor, whereas the short isoform (PR-minus) functions as an oncogene; a clear example is provided by PRDM2 [ 25 , 27 ].…”