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]

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).^[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

References