PDF(Pubmed)
Abstract：
DNA methylation maintenance is essential for cell fate inheritance. In differentiated cells, this involves orchestrated actions of DNMT1 and UHRF1. In mice, the high-affinity binding of DPPA3 to the UHRF1 PHD finger regulates UHRF1 chromatin dissociation and cytosolic localization, which is required for oocyte maturation and early embryo development. However, the human DPPA3 ortholog functions during these stages remain unclear. Here, we report the structural basis for human DPPA3 binding to the UHRF1 PHD finger. The conserved human DPPA3 85VRT87 motif binds to the acidic surface of UHRF1 PHD finger, whereas mouse DPPA3 binding additionally utilizes two unique α-helices. The binding affinity of human DPPA3 for the UHRF1 PHD finger was weaker than that of mouse DPPA3. Consequently, human DPPA3, unlike mouse DPPA3, failed to inhibit UHRF1 chromatin binding and DNA remethylation in Xenopus egg extracts effectively. Our data provide novel insights into the distinct function and structure of human DPPA3.
摘要：
DNA甲基化维持对于细胞命运遗传至关重要。在分化的细胞中，这涉及DNMT1和UHRF1的协调行动。在老鼠身上,DPPA3与UHRF1PHD指的高亲和力结合调节UHRF1染色质解离和胞质定位，这是卵母细胞成熟和早期胚胎发育所必需的。然而,在这些阶段，人类DPPA3直系同源功能仍不清楚。这里,我们报告了人DPPA3与UHRF1PHD手指结合的结构基础。保守的人DPPA385VRT87基序与UHRF1PHD手指的酸性表面结合，而小鼠DPPA3结合另外利用两个独特的α-螺旋。人DPPA3对UHRFlPHD指的结合亲和力弱于小鼠DPPA3。因此,与小鼠DPPA3不同，人DPPA3未能有效抑制非洲爪鱼卵提取物中的UHRF1染色质结合和DNA再甲基化。我们的数据为人类DPPA3的独特功能和结构提供了新的见解。
