PRDM9

Last updated

PRDM9
Available structures
PDB Ortholog search: PDBe RCSB
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
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
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
View/Edit Human View/Edit Mouse

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]

Contents

Domain Architecture

Schematic of the PRDM9 Domain Architecture in mice PRDM9 Domain Architecture.png
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

Related Research Articles

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Chromosomal crossover, or crossing over, is the exchange of genetic material during sexual reproduction between two homologous chromosomes' non-sister chromatids that results in recombinant chromosomes. It is one of the final phases of genetic recombination, which occurs in the pachytene stage of prophase I of meiosis during a process called synapsis. Synapsis begins before the synaptonemal complex develops and is not completed until near the end of prophase I. Crossover usually occurs when matching regions on matching chromosomes break and then reconnect to the other chromosome.

<span class="mw-page-title-main">Genetic recombination</span> Production of offspring with combinations of traits that differ from those found in either parent

Genetic recombination is the exchange of genetic material between different organisms which leads to production of offspring with combinations of traits that differ from those found in either parent. In eukaryotes, genetic recombination during meiosis can lead to a novel set of genetic information that can be further passed on from parents to offspring. Most recombination occurs naturally and can be classified into two types: (1) interchromosomal recombination, occurring through independent assortment of alleles whose loci are on different but homologous chromosomes ; & (2) intrachromosomal recombination, occurring through crossing over.

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<span class="mw-page-title-main">BRCA2</span> Gene known for its role in breast cancer

BRCA2 and BRCA2 are human genes and their protein products, respectively. The official symbol and the official name are maintained by the HUGO Gene Nomenclature Committee. One alternative symbol, FANCD1, recognizes its association with the FANC protein complex. Orthologs, styled Brca2 and Brca2, are common in other vertebrate species. BRCA2 is a human tumor suppressor gene, found in all humans; its protein, also called by the synonym breast cancer type 2 susceptibility protein, is responsible for repairing DNA.

<span class="mw-page-title-main">Homologous recombination</span> Genetic recombination between identical or highly similar strands of genetic material

Homologous recombination is a type of genetic recombination in which genetic information is exchanged between two similar or identical molecules of double-stranded or single-stranded nucleic acids.

Recombination hotspots are regions in a genome that exhibit elevated rates of recombination relative to a neutral expectation. The recombination rate within hotspots can be hundreds of times that of the surrounding region. Recombination hotspots result from higher DNA break formation in these regions, and apply to both mitotic and meiotic cells. This appellation can refer to recombination events resulting from the uneven distribution of programmed meiotic double-strand breaks.

<span class="mw-page-title-main">CHEK2</span> Protein-coding gene in humans

CHEK2 is a tumor suppressor gene that encodes the protein CHK2, a serine-threonine kinase. CHK2 is involved in DNA repair, cell cycle arrest or apoptosis in response to DNA damage. Mutations to the CHEK2 gene have been linked to a wide range of cancers.

<span class="mw-page-title-main">Spo11</span> Protein-coding gene in the species Homo sapiens

Spo11 is a protein that in humans is encoded by the SPO11 gene. Spo11, in a complex with mTopVIB, creates double strand breaks to initiate meiotic recombination. Its active site contains a tyrosine which ligates and dissociates with DNA to promote break formation. One Spo11 protein is involved per strand of DNA, thus two Spo11 proteins are involved in each double stranded break event.

<span class="mw-page-title-main">Translin</span> Protein-coding gene in the species Homo sapiens

Translin is a DNA-binding protein that in humans is encoded by the TSN gene. Together with translin-associated factor X, translin forms the component 3 of promoter of RISC (C3PO) complex which facilitates endonucleolytic cleavage of the passenger strand during microRNA loading into the RNA-induced silencing complex (RISC).

<span class="mw-page-title-main">DMC1 (gene)</span> Protein-coding gene in the species Homo sapiens

Meiotic recombination protein DMC1/LIM15 homolog is a protein that in humans is encoded by the DMC1 gene.

<span class="mw-page-title-main">SNTG1</span> Protein-coding gene in the species Homo sapiens

Gamma-1-syntrophin is a protein that in humans is encoded by the SNTG1 gene.

<span class="mw-page-title-main">RMI1</span> Protein-coding gene in the species Homo sapiens

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<span class="mw-page-title-main">BRDT</span> Protein-coding gene in the species Homo sapiens

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<span class="mw-page-title-main">HORMAD1</span> Protein-coding gene in the species Homo sapiens

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Fanconi anemia, complementation group M, also known as FANCM is a human gene. It is an emerging target in cancer therapy, in particular cancers with specific genetic deficiencies.

<span class="mw-page-title-main">Meiotic recombination checkpoint</span>

The meiotic recombination checkpoint monitors meiotic recombination during meiosis, and blocks the entry into metaphase I if recombination is not efficiently processed.

<span class="mw-page-title-main">Protein ZGRF1</span> Protein-coding gene in the species Homo sapiens

Protein ZGRF1 is a protein encoded in the human by the ZGRF1 gene also known as C4orf21, that has a weight of 236.6 kDa. The ZGRF1 gene product localizes to the cell nucleus and promotes DNA repair by stimulating homologous recombination. This gene shows relatively low expression in most human tissues, with increased expression in situations of chemical dependence. ZGRF1 is orthologous to nearly all eukaryotes. Functional domains of this protein link it to a series of helicases, most notably the AAA_12 and AAA_11 domains.

H3K36me3 is an epigenetic modification to the DNA packaging protein Histone H3. It is a mark that indicates the tri-methylation at the 36th lysine residue of the histone H3 protein and often associated with gene bodies.

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Further reading

This article incorporates text from the United States National Library of Medicine, which is in the public domain.