Akter Mahmuda, Lyu Xiaoai, Lu Jiaxing, Wang Xiao, Phonesavanh Tyson, Wang Hao, Yu Hongtao, Kang Jungseog
Arts and Science, New York University at Shanghai, Shanghai, China.
School of Life Sciences, Westlake University, Hangzhou, Zhejiang, China Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang, China.
J Biol Chem. 2025 May;301(5):108464. doi: 10.1016/j.jbc.2025.108464. Epub 2025 Mar 28.
The genome stability of eukaryotic cells is ensured by proper regulation of histones and their variants. H2A.Z, a conserved and essential histone H2A variant, plays a crucial role in this process by regulating various chromatin-related processes such as gene expression, heterochromatin formation, DNA damage repair, and chromosome segregation. It has two isoforms, H2A.Z1 and H2A.Z2, also known as H2AFZ and H2AFV, respectively, which perform both redundant and nonredundant roles in maintaining genome stability. In this study, we investigated the isoform-specific mitotic functions of H2A.Z in HeLa cells. Our studies revealed that the depletion of H2AFV or H2AFZ did not alter the overall cell cycle profile. However, H2AFV depletion significantly increased the formation of micronuclei, indicating defects in chromosome segregation. Additionally, H2AFV depletion led to the accumulation of DNA damage at various nuclear loci including centromeres. Interestingly, we discovered that H2AFV depletion significantly increased centromeric transcription, which may interfere with proper centromere function. Furthermore, we discovered that a mitotic kinase, Aurora B, binds to both H2AFV and H2AFZ, but preferentially to H2AFV. Inhibition of Aurora B activity by hesperadin disrupted proper centromeric transcription but not significantly centromeric localization of H2A.Z. Collectively, these data demonstrated that the H2A.Z isoforms play distinctive regulatory roles in maintaining proper centromeric transcription and DNA repair, ensuring accurate chromosome segregation.
真核细胞的基因组稳定性通过组蛋白及其变体的适当调控得以确保。H2A.Z是一种保守且必需的组蛋白H2A变体，通过调控各种与染色质相关的过程，如基因表达、异染色质形成、DNA损伤修复和染色体分离，在这一过程中发挥关键作用。它有两种亚型，H2A.Z1和H2A.Z2，也分别称为H2AFZ和H2AFV，它们在维持基因组稳定性方面发挥着冗余和非冗余的作用。在本研究中，我们调查了H2A.Z在HeLa细胞中的亚型特异性有丝分裂功能。我们的研究表明，H2AFV或H2AFZ的缺失并未改变整体细胞周期谱。然而，H2AFV的缺失显著增加了微核的形成，表明染色体分离存在缺陷。此外，H2AFV的缺失导致包括着丝粒在内的各个核位点的DNA损伤积累。有趣的是，我们发现H2AFV的缺失显著增加了着丝粒转录，这可能会干扰着丝粒的正常功能。此外，我们发现一种有丝分裂激酶Aurora B与H2AFV和H2AFZ都结合，但优先与H2AFV结合。橙皮素对Aurora B活性的抑制破坏了着丝粒的正常转录，但对H2A.Z的着丝粒定位没有显著影响。总的来说，这些数据表明H2A.Z亚型在维持适当的着丝粒转录和DNA修复、确保准确的染色体分离方面发挥着独特的调控作用。
