PRDM9

Description

The PRDM9 (PR/SET domain 9) is a protein-coding gene located on chromosome 5.

PR domain zinc finger protein 9 is a protein that in humans is encoded by the PRDM9 gene. PRDM9 is responsible for positioning recombination hotspots during meiosis by binding a DNA sequence motif encoded in its zinc finger domain. PRDM9 is the only speciation gene found so far in mammals, and is one of the fastest evolving genes in the genome.

== Domain Architecture ==

PRDM9 has multiple domains including KRAB domain, SSXRD, PR/SET domain (H3K4 & H3K36 trimethyltransferase), and an array of C2H2 Zinc Finger domains (DNA binding).

== History == In 1974 Jiri Forejt and P. Ivanyi identified a locus which they named Hst1 which controlled hybrid sterility. In 1982 a haplotype was identified controlling recombination rate wm7, which would later be identified as PRDM9. In 1991 a protein binding to the minisatelite consensus sequence 5′-CCACCTGCCCACCTCT-3′ was detected and partially purified (named Msbp3 - minisatelite binding protein 3). This would later turn out to be the same PRDM9 protein independently identified later. In 2005 a gene was identified (named Meisetz) that is required for progression through meiotic prophase and has H3K4 methyltransferase activity. In 2009 Jiri Forejt and colleagues identified Hst1 as Meisetz/PRDM9 - the first and so far only speciation gene in mammals.

PRDM9 is a histone methyltransferase that sequentially mono-, di-, and tri-methylates both ‘Lys-4‘ (H3K4) and ‘Lys-36‘ (H3K36) of histone H3, producing trimethylated ‘Lys-4‘ (H3K4me3) and trimethylated ‘Lys-36‘ (H3K36me3) histone H3. This plays a key role in meiotic prophase by determining hotspot localization and promoting meiotic recombination. PRDM9 can also methylate all four core histones, with H3 being the best substrate. Additionally, PRDM9 can mono- and di-methylate H4K20 and trimethylate H3K9, with di-methylated H3K9 being the best substrate. During meiotic prophase, PRDM9 binds specific DNA sequences through its zinc finger domains, promoting local H3K4me3 and H3K36me3 enrichment on the same nucleosomes through its histone methyltransferase activity. This promotes double-stranded breaks (DSB) formation at PRDM9-binding sites, initiating meiotic recombination for proper meiotic progression. Hotspot-bound PRDM9 interacts with several complexes during meiotic progression: it binds CDYL and EHMT2 in early leptonema, followed by EWSR1 and CXXC1 by the end of leptonema. EWSR1 joins PRDM9 with the chromosomal axis through REC8. This controls the DSB repair pathway, pairing of homologous chromosomes, and sex body formation. PRDM9 also plays a central role in the transcriptional activation of genes during early meiotic prophase due to H3K4me3 and H3K36me3 enrichment, which represents a specific tag for epigenetic transcriptional activation. PRDM9 can also perform automethylation. Acetylation and phosphorylation of histone H3 attenuate or prevent histone H3 methylation. PRDM9 is a homodimer and interacts with EHMT2 and CDYL, but only when PRDM9 is bound to hotspot DNA. It also interacts with CXXC1, but this interaction doesn‘t link PRDM9-activated recombination hotspot sites with DSB machinery and is not required for hotspot recognition. PRDM9 forms a complex with EWSR1, REC8, SYCP3, and SYCP1; complex formation depends on the phosphorylated form of REC8 and requires PRDM9 bound to hotspot DNA. EWSR1 joins PRDM9 with the chromosomal axis through REC8.

PRDM9 is also known as KMT8B, MEISETZ, MSBP3, PFM6, ZNF899.

Associated Diseases

WES Whole Exome Sequencing

Clinical Exome Sequencing