The histone modification reader ZCWPW1 promotes double-strand break repair by regulating cross-talk of histone modifications and chromatin accessibility at meiotic hotspots

Abstract

Background The PRDM9-dependent histone methylation H3K4me3 and H3K36me3 function in assuring accurate homologous recombination at recombination hotspots in mammals. Beyond histone methylation, H3 lysine 9 acetylation (H3K9ac) is also greatly enriched at recombination hotspots. Previous work has indicated the potential cross-talk between H3K4me3 and H3K9ac at recombination hotspots, but it is still unknown what molecular mechanisms mediate the cross-talk between the two histone modifications at hotspots or how the cross-talk regulates homologous recombination in meiosis. Results Here, we find that the histone methylation reader ZCWPW1 is essential for maintaining H3K9ac by antagonizing HDAC proteins’ deacetylation activity and further promotes chromatin openness at recombination hotspots thus preparing the way for homologous recombination during meiotic double-strand break repair. Interestingly, ectopic expression of the germ-cell-specific protein ZCWPW1 in human somatic cells enhances double-strand break repair via homologous recombination. Conclusions Taken together, our findings provide new insights into how histone modifications and their associated regulatory proteins collectively regulate meiotic homologous recombination.

Recent advances in mechanisms ensuring the pairing, synapsis and segregation of XY chromosomes in mice and humans

“…Beyond H3K4me3 and H3K36me3, H3 lysine 9 acetylation (H3K9ac) is also enriched concurrently at recombination autosomal hotspots. H3K9ac also promotes chromatin openness, enabling DSB repair by homologous recombination [ 82 ]. On this regard The H3K4me3 and H3K36me3 reader ZCWPW1 (Zinc Finger CW-Type and PWWP Domain Containing 1) is recruited to recombination hotspots by PRDM9 and is essential for the execution of early repair steps at DSBs hotspots, by antagonizing histone deacetylase proteins [ 82 – 85 ].…”

“…H3K9ac also promotes chromatin openness, enabling DSB repair by homologous recombination [ 82 ]. On this regard The H3K4me3 and H3K36me3 reader ZCWPW1 (Zinc Finger CW-Type and PWWP Domain Containing 1) is recruited to recombination hotspots by PRDM9 and is essential for the execution of early repair steps at DSBs hotspots, by antagonizing histone deacetylase proteins [ 82 – 85 ]. In mouse, the PAR region contains a large H3K4me3 hotspot [ 75 ], which, however, is generated independently of PRDM9 [ 75 ].…”

Epigenetic regulation of diverse cell death modalities in cancer: a focus on pyroptosis, ferroptosis, cuproptosis, and disulfidptosis

“…Histone modification writers include lysine methyltransferases (KMTs), protein arginine methyltransferases (PRMTs), lysine acetyltransferases (KATs or HATs), histone ubiquitin ligases, histone kinases [145]. Histone modification readers include chromodomain, Tudor domain, MBT domain, PhD finger, bromodomain-containing proteins [146]. Histone modification erasers are lysine demethylases (KDMs), histone deacetylases (HDACs and SIRTs), histone deubiquitinating enzymes, and histone phosphatases [144,147].…”

Meiotic Recognition of Evolutionarily Diverged Homologs: Chromosomal Hybrid Sterility Revisited

“…The PRDM9 hotspots localized on 250–500 kb long DNA loops of leptotene spermatocytes ( Grey and de Massy 2021 ) are pulled down to the chromosome axis to be processed by the SPO11 DNA DSB machinery. Recently the ZCWPW1 protein, a reader of the H3K4 and H3K36 methylation, and the CXXC1 protein were proposed to participate in this step ( Parvanov et al 2017 ; Wells et al 2020 ; Cavassim et al 2022 ; Yuan et al 2022 ). However, the regulation of these processes on a genome-wide level still needs to be clarified.…”