Role of PRDM9 KRAB Domain in Meiotic DSB Site Determination

DING Jian¹, LIN Zhen², TONG Minghan^1,2*

(¹Key Laboratory of Systems Health Science of Zhejiang Province, School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China; ²State Key Laboratory of Molecular Biology, Shanghai Key Laboratory of Molecular Andrology, CAS Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China)

Abstract:

Homologous recombination plays a crucial role in meiosis and is vital for ensuring the correct segregation of homologous chromosomes and genetic diversity. Recombination sites are not randomly distributed throughout the genome, but are limited to specific regions known as “recombination hotspots”. In most mammals, PRDM9 mediates the determination of recombination hotspots. PRDM9 recognizes a specific binding sequence on the chromosome, catalyzes the nucleosome H3K4me3 modification near the sequence, and then guides SPO11 to produce programmed DNA double-strand breaks. PRDM9 comprises three conserved structural domains: the zinc finger domain, responsible for specific DNA binding; the PR/SET domain, catalyzing H3K4me3 modification; and the KRAB domain, whose function is currently unclear. This study found that truncation of the KRAB domain of PRDM9 in mice results in the loss of its function, impeding meiotic prophase and gametogenesis. The researchers also identified that the KRAB domain is essential for the methyltransferase activity of PRDM9 and is involved in the regulation of meiotic DSB formation at PRDM9-dependent hotspots.

CSTR: 32200.14.cjcb.2023.05.0004