The remodeling of Z-DNA in the mammalian germ line.
The remodeling of Z-DNA in the mammalian germ line.
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DOI：
10.1042/bst20221015
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发表时间：
2022-12-16
影响因子：
3.9
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中科院分区：
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我们最近发现了一种新的生物学过程，即发育中的胎鼠雄性生殖细胞中Z-DNA结构的预定重塑[Nat. Cell Biol.24，1141-1153]。这个过程影响嘌呤/嘧啶二核苷酸重复序列（PPR）丰富的序列，可以形成稳定的左手Z-DNA结构。执行此功能的蛋白质被鉴定为ZBTB 43，ZBTB蛋白质大家族的成员。ZBTB 43的Z-DNA重塑不仅与男性生殖系中DNA甲基化和染色质事件的整体重塑相一致，而且它也是从头DNA甲基化的先决条件。当ZBTB 43将DNA结构从左手Z形Z-DNA改变为规则光滑的右手B-DNA时，它也为从头DNA甲基转移酶DNMT 3A产生合适的底物。ZBTB 43通过指导原核细胞中PPR的从头DNA甲基化，保护了雄性配子的表观基因组完整性。PPR是脆弱的序列，是哺乳动物细胞中大的缺失和重排位点，这种脆弱性被认为是由于Z-DNA结构的形成而不是序列本身。这一想法现在得到了体内发现的支持，即DNA双链断裂在缺乏ZBTB 43依赖性Z-DNA重塑的突变体原核细胞中积累。如果未修复，双链DNA断裂可能导致生殖细胞突变。因此，通过防止这种断裂，ZBTB 43对于保护世代之间的基因组稳定性至关重要。在这里，我们将更详细地讨论这些发现的意义和影响。
We recently discovered a novel biological process, the scheduled remodeling of Z-DNA structures in the developing fetal mouse male germ cells [Nat. Cell Biol. 24, 1141–1153]. This process affects purine/pyrimidine dinucleotide repeat (PPR) rich sequences, which can form stable left-handed Z-DNA structures. The protein that carries out this function is identified as ZBTB43, member of a large family of ZBTB proteins. Z-DNA remodeling by ZBTB43 not only coincides with global remodeling of DNA methylation and chromatin events in the male germ line, but it also is a prerequisite for de novo DNA methylation. When ZBTB43 changes DNA structure from the left-handed zigzag shaped Z-DNA to the regular smooth right-handed B-DNA, it also generates a suitable substrate for the de novo DNA methyltransferase, DNMT3A. By instructing de novo DNA methylation at PPRs in prospermatogonia, ZBTB43 safeguards epigenomic integrity of the male gamete. PPRs are fragile sequences, sites of large deletions and rearrangements in mammalian cells, and this fragility is thought to be due to Z-DNA structure formation rather than the sequence itself. This idea is now supported by the in vivo finding that DNA double strand breaks accumulate in mutant prospermatogonia which lack ZBTB43-dependent Z-DNA remodeling. If unrepaired, double stranded DNA breaks can lead to germ line mutations. Therefore, by preventing such breaks ZBTB43 is critical for guarding genome stability between generations. Here, we discuss the significance and implications of these findings in more detail.