Orchestrating recombination initiation in mice and men

Recent discoveries have advanced our understanding of recombination initiation beyond the placement of double-stranded DNA breaks (DSBs) from germline replication timing to the dynamic reorganization of chromatin, and defined critical players of recombination initiation. This article focuses on recombination initiation in mammals utilizing the PRDM9 protein to orchestrate crucial stages of meiotic recombination initiation by interacting with the local DNA environment and several protein complexes. The Pioneer Complex with the SNF2-type chromatin remodeling enzyme HELLS, exposes PRDM9-bound DNA. At the same time, a Compass-Complex containing EWSR1, CXXC1, CDYL, EHMT2 and PRDM9 facilitates the association of putative hotspot sites in DNA loops with the chromosomal axis where DSB-promoting complexes are located, and DSBs are catalyzed by the SPO11/TOPOVIBL complex. Finally, homology search is facilitated at PRDM9-directed sites by ANKRD31. The Reader-Writer system consists of PRDM9 writing characteristic histone methylation signatures, which are read by ZCWPW1, promoting efficient homology engagement.