This entry represents the PR/SET domain found in PR domain zinc finger protein 7 and 9 (PRDM7/9). PRDM7 (also termed PR domain-containing protein 7) is a primate-specific histone methyltransferase that is the result of a recent gene duplication of PRDM9. It selectively catalyses the trimethylation of H3 lysine 4 (H3K4me3) []. PRDM9 (also termed PR domain-containing protein 9) is a histone methyltransferase that specifically trimethylates 'Lys-4' of histone H3 (H3K4me3) during meiotic prophase and is essential for proper meiotic progression. It also efficiently mono-, di-, and trimethylates H3K36. Aberrant PRDM9 expression is associated with genome instability in cancer [, , , ]. PRDM9 has also been shown to be able to performs intramolecular automethylation on multiple lysine residues localised to a lysine-rich region on the post-SET domain [].The PRDM family members are characterised by the presence of a N-terminal PR (PRDI-BF1 and RIZ1 homology) domain followed by multiple zinc fingers which confer DNA binding activity. PR domains are only distantly related to the classical SET methyltransferase domains []. They are involved in epigenetic regulation of gene expression through their intrinsic histone methyltransferase activity or via interactions with other chromatin modifying enzymes [].
This is a zinc knuckle motif found in PRDM4 (Schwann cell factor 1, SC-1), a member of the PR protein family. PRDM4 is a transcriptional regulator that has been implied in transduction of nerve growth factor signals via the p75 neurotrophin receptor and in cell growth arrest. The short motif is also present in several other PR proteins including human PRDM6 (PRISM), PRDM7, PRDM9 (meisetz), PRDM10 (tristanin), PRDM11, and PRDM15. The conservation of cysteine and histidine residues suggested that this 20 amino acid motif binds zinc, hence the name 'PR zinc knuckle' to distinguish it from the longer (30 amino acid) C2H2-like zinc fingers that are located C-terminally of the PR domain. The PR zinc knuckle fold is similar to that of Gag-knuckles (a β-hairpin providing two zinc ligands followed by a short helix or a loop providing the other two zinc ligands) and zinc ribbons (two β-hairpins, each providing two zinc ligands) [].
This domain of about 70 amino acid residues is related to the Krueppel-associated box (KRAB) domain and has been recently stratified as the ancestral KRAB domain (aKRAB). Sequence analysis revealed that these sequences have a motif that can also be traced in invertebrates, whose homologues still exist in mammals, including humans, in the PR/SET domain 9 (PRDM9) and synovial sarcoma X breakpoint (SSX) orthologous and paralogous groups []. This domain is found in the N-terminal ends of PRDM9 and proteins belonging to the SSX family [, , ]. Proteins of the SSX family lack the C2H2-type zinc finger which is invariably found in proteins containing the KRAB domain.Although the aKRAB domains of SSX1 and SSX2 contribute to the repressive activity of these proteins, transcriptional repression is mainly mediated by an auxiliary region located in their C terminus, called KRAB-B []. Hence, unlike the canonical KRAB domain, the aKRAB domain is only a weak transcriptional repression domain, as seen in human PRDM9, which neither silences transcription nor interacts with TRIM28/KAP1 [, ].
