Capital Normal University College of Life Science, Beijing, China.
Department of Epigenetics, Van Andel Institute, Grand Rapids, MI, USA.
Nat Cell Biol. 2022 Jul;24(7):1141-1153. doi: 10.1038/s41556-022-00941-9. Epub 2022 Jul 4.
Mutagenic purine-pyrimidine repeats can adopt the left-handed Z-DNA conformation. DNA breaks at potential Z-DNA sites can lead to somatic mutations in cancer or to germline mutations that are transmitted to the next generation. It is not known whether any mechanism exists in the germ line to control Z-DNA structure and DNA breaks at purine-pyrimidine repeats. Here we provide genetic, epigenomic and biochemical evidence for the existence of a biological process that erases Z-DNA specifically in germ cells of the mouse male foetus. We show that a previously uncharacterized zinc finger protein, ZBTB43, binds to and removes Z-DNA, preventing the formation of DNA double-strand breaks. By removing Z-DNA, ZBTB43 also promotes de novo DNA methylation at CG-containing purine-pyrimidine repeats in prospermatogonia. Therefore, the genomic and epigenomic integrity of the species is safeguarded by remodelling DNA structure in the mammalian germ line during a critical window of germline epigenome reprogramming.
突变嘌呤-嘧啶重复序列可以采用左手 Z-DNA 构象。潜在 Z-DNA 位点的 DNA 断裂可导致癌症中的体细胞突变，或导致传递给下一代的种系突变。目前尚不清楚种系中是否存在控制嘌呤-嘧啶重复序列中 Z-DNA 结构和 DNA 断裂的机制。在这里，我们提供遗传、表观基因组学和生化证据，证明在雄性胎鼠的生殖细胞中存在一种生物过程，可以特异性地清除 Z-DNA。我们表明，一种以前未被表征的锌指蛋白 ZBTB43 结合并去除 Z-DNA，从而阻止 DNA 双链断裂的形成。通过去除 Z-DNA，ZBTB43 还促进了 CG 富含嘌呤-嘧啶重复序列在精原细胞中的从头 DNA 甲基化。因此，通过在生殖细胞表观基因组重编程的关键窗口期重塑哺乳动物生殖细胞中的 DNA 结构，保障了物种的基因组和表观基因组完整性。
