PRDM9 and Its Role in Genetic Recombination

Abstract

PRDM9 is a zinc finger protein that binds DNA at specific locations in the genome where it trimethylates histone H3 at lysines 4 and 36 at surrounding nucleosomes. During meiosis in many species, including humans and mice where PRDM9 has been most intensely studied, these actions determine the location of recombination hotspots, where genetic recombination occurs. In addition, PRDM9 facilitates the association of hotspots with the chromosome axis, the site of the programmed DNA double-strand breaks (DSBs) that give rise to genetic exchange between chromosomes. In the absence of PRDM9 DSBs are not properly repaired. Collectively, these actions determine patterns of genetic linkage and the possibilities for chromosome reorganization over successive generations.

Keywords: PRDM9; meiosis; recombination.

Figure 1. Molecular structure of PRDM9

A. The unique composition of the PRDM9 protein consisting of a KRAB-like, SSXRD, SET, and zinc finger array domains. The amino acid residues at -1, 3, and 6 positions relative to the α helix in each finger are responsible for the contact with DNA and are shown within the fingers. Human A and mouse Dom2 and protein variants are shown. B. Composition of the tandem zinc finger array of the major human and mouse Prdm9/PRDM9 alleles. Individual fingers are presented as colored squares. The colors reflect differences in the amino acid residues at -1,3, and 6 positions. The boxes encompass the fingers that contribute to the principal motif of each allele [–38, 47]. Human A allele binds a principal motif CCxCCxTxxCC with fingers 8–11 [41]. Mouse Dom2 allele binds a principal motif Gx(T/A)GxT(G/A)CT(G/A)(C/T)(C/T) with fingers 3–7 [47].

Figure 2. PRDM9 binding, nucleosome modification, repositioning, and DSB initiation

PRDM9 binding sites can be determined in vitro (Affinity-seq, red [45]) and in vivo (PRDM9 ChIP-seq, blue [47]). Its subsequent histone trimethylation at nearby nucleosomes (H3K4me3, blue; H3K36me3, orange [35]) limits the space in which double strand break initiation will occur (DMC1, purple [49]). The nucleosome repositioning after PRDM9 trimethylation of H3K4 and H3K36 is presented above the main panel.