PRDM9

PR domain^{[note 1]} zinc finger protein 9 is a protein that in humans is encoded by the PRDM9 gene.^[5] PRDM9 is responsible for positioning recombination hotspots during meiosis by binding a DNA sequence motif encoded in its zinc finger domain.^[6] PRDM9 is the only speciation gene found so far in mammals, and is one of the fastest evolving genes in the genome.^[7][8]

PRDM9
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 4IJD, 5EGB, 5EH2, 5EI9
Identifiers
Aliases	PRDM9, MEISETZ, MSBP3, PFM6, PRMD9, ZNF899, PR domain 9, PR/SET domain 9, KMT8B
External IDs	OMIM: 609760; MGI: 2384854; HomoloGene: 104139; GeneCards: PRDM9; OMA:PRDM9 - orthologs
Gene location (Human) Chr. Chromosome 5 (human)[1] Band 5p14.2 Start 23,443,586 bp[1] End 23,528,093 bp[1]
Gene location (Mouse) Chr. Chromosome 17 (mouse)[2] Band 17|17 A2 Start 15,543,079 bp[2] End 15,564,354 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in testicle gonad right testis left testis sural nerve corpus callosum mononuclear cell monocyte granulocyte bone Top expressed in neural layer of retina granulocyte muscle of thigh zygote lip tail of embryo spermatid right kidney morula embryo More reference expression data BioGPS n/a
Gene ontology Molecular function methyltransferase activity transferase activity metal ion binding nucleic acid binding DNA-binding transcription factor activity, RNA polymerase II-specific recombination hotspot binding histone-lysine N-methyltransferase activity sequence-specific DNA binding RNA polymerase II transcription regulatory region sequence-specific DNA binding chromatin DNA binding histone methyltransferase activity (H3-K4 specific) DNA-binding transcription factor activity Cellular component nucleoplasm intracellular anatomical structure nucleus chromosome Biological process meiotic gene conversion positive regulation of reciprocal meiotic recombination histone lysine methylation methylation regulation of transcription, DNA-templated meiosis transcription, DNA-templated chromatin organization regulation of transcription by RNA polymerase II histone H3-K4 methylation Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 56979 213389 Ensembl ENSG00000164256 ENSMUSG00000051977 UniProt Q9NQV7 E9Q4V2 RefSeq (mRNA) NM_020227 NM_001310214 NM_001376900 NM_144809 NM_001361436 RefSeq (protein) NP_001297143 NP_064612 NP_001363829 NP_659058 NP_001348365 Location (UCSC) Chr 5: 23.44 – 23.53 Mb Chr 17: 15.54 – 15.56 Mb PubMed search [3] [4]
Wikidata
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Domain Architecture

Schematic of the PRDM9 Domain Architecture in mice

PRDM9 has multiple domains including KRAB domain, SSXRD, PR/SET domain (H3K4 & H3K36 trimethyltransferase), and an array of C2H2 Zinc Finger domains (DNA binding).^[9]

History

In 1974 Jiri Forejt and P. Ivanyi identified a locus which they named Hst1 which controlled hybrid sterility.^[10]

In 1982 a haplotype was identified controlling recombination rate wm7,^[11] which would later be identified as PRDM9.^[12]

In 1991 a protein binding to the minisatelite consensus sequence 5′-CCACCTGCCCACCTCT-3′ was detected and partially purified (named Msbp3 - minisatelite binding protein 3).^[13] This would later turn out to be the same PRDM9 protein independently identified later.^[14]

In 2005 a gene was identified (named Meisetz) that is required for progression through meiotic prophase and has H3K4 methyltransferase activity.^[15]

In 2009 Jiri Forejt and colleagues identified Hst1 as Meisetz/PRDM9 - the first and so far only speciation gene in mammals.^[16]

Later in 2009 PRDM9 was identified as one of the fastest evolving genes in the genome.^[9][17]

In 2010 three groups independently identified PRDM9 as controlling the positioning of recombination hotspots in humans and mice.^{[6][18][19][20][21]}

in 2012 it was shown that almost all hotspots are positioned by PRDM9 and that in its absence hotspots form near promoters.^[22]

In 2014 it was reported that the PRDM9 SET domain could also trimethylate H3K36 in vitro,^[23] which was confirmed in vivo in 2016.^[24]

In 2016 it was shown that the hybrid sterility caused by PRDM9 can be reversed and that the sterility is caused by asymmetric double strand breaks.^[25][26]

Function in Recombination

PRDM9 mediates the process of meiosis by directing the sites of homologous recombination.^[27] In humans and mice, recombination does not occur evenly throughout the genome but at particular sites along the chromosomes called recombination hotspots. Hotspots are regions of DNA about 1–2kb in length.^[28] There are approximately 30,000 to 50,000 hotspots within the human genome corresponding to one for every 50–100kb DNA on average.^[28] In humans, the average number of crossover recombination events per hotspot is one per 1,300 meioses, and the most extreme hotspot has a crossover frequency of one per 110 meioses.^[28] These hotspots are binding sites for the PRDM9 Zinc Finger array.^[29] Upon binding to DNA, PRDM9 catalyzes trimethylation of Histone 3 at lysine 4 and lysine 36.^[30] As a result, local nucleosomes are reorganized and through an unknown mechanism the recombination machinery is recruited to form double strand breaks.

Notes

1. positive-regulatory domain