Rodriguez Alyssa A, Cirulli Alessandro E, Chau Katie, Nguyen Justin, Ye Qiaozhen, Corbett Kevin D
Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA, USA.
Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, CA, USA.
Life Sci Alliance. 2025 Aug 19;8(11). doi: 10.26508/lsa.202503428. Print 2025 Nov.
In meiosis, ploidy reduction is driven by a complex series of DNA breakage and recombination events between homologous chromosomes, orchestrated by meiotic HORMA domain proteins (HORMADs). Meiotic HORMADs possess a central chromatin binding region (CBR) whose architecture varies across eukaryotic groups. Here, we determine high-resolution crystal structures of the meiotic HORMAD CBR from two diverged aquatic Holozoa, and , which reveal tightly associated plant homeodomain (PHD) and winged helix-turn-helix (wHTH) domains. We show that PHD-wHTH CBRs bind duplex DNA through their wHTH domains, and identify key residues that disrupt this interaction. Combining experimental and predicted structures, we show that the CBRs' PHDs likely interact with the tail of histone H3, and may discriminate between unmethylated and trimethylated H3 lysine 4. Finally, we show that Holozoa Hop1 CBRs bind nucleosomes in vitro in a bipartite manner involving both the PHD and wHTH domain. Our data reveal how meiotic HORMADs with PHD-wHTH CBRs can bind chromatin and potentially discriminate between chromatin states to drive meiotic recombination to specific chromosomal regions.
在减数分裂中，倍性降低是由同源染色体之间一系列复杂的DNA断裂和重组事件驱动的，这些事件由减数分裂HORMA结构域蛋白（HORMADs）精心编排。减数分裂HORMADs拥有一个中央染色质结合区域（CBR），其结构在不同真核生物类群中有所不同。在这里，我们确定了来自两种不同的水生全动物亚界生物—— 和 的减数分裂HORMAD CBR的高分辨率晶体结构，这些结构揭示了紧密相连的植物同源结构域（PHD）和翼状螺旋-转角-螺旋（wHTH）结构域。我们表明，PHD-wHTH CBRs通过其wHTH结构域结合双链DNA，并鉴定出破坏这种相互作用的关键残基。结合实验结构和预测结构，我们表明CBRs的PHD可能与组蛋白H3的尾部相互作用，并可能区分未甲基化和三甲基化的H3赖氨酸4。最后，我们表明全动物亚界生物的Hop1 CBRs在体外以一种涉及PHD和wHTH结构域的二分方式结合核小体。我们的数据揭示了具有PHD-wHTH CBRs的减数分裂HORMADs如何结合染色质，并可能区分染色质状态，从而将减数分裂重组驱动到特定的染色体区域。
