Pwp1 regulates telomere length by stabilizing shelterin complex and maintaining histone H4K20 trimethylation
Pwp1 regulates telomere length by stabilizing shelterin complex and maintaining histone H4K20 trimethylation
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Pwp1 通过稳定庇护蛋白复合物和维持组蛋白 H4K20 三甲基化来调节端粒长度
DOI：
10.1038/s41421-019-0116-8
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发表时间：
2019
期刊：
影响因子：
33.5
通讯作者：
Kang Jiuhong
中科院分区：
文献类型：
--
作者：
Yu Yangyang;Jia Wenwen;Lyu Yao;Su Dingwen;Bai Mingliang;Shen Junwei;Qiao Jing;Han Tong;Liu Wenqiang;Chen Jiayu;Chen Wen;Ye Dan;Guo Xudong;Zhu Songcheng;Xi Jiajie;Zhu Ruixin;Wan Xiaoping;Gao Shaorong;Zhu Jiyue;Kang Jiuhong
端粒的维持对染色体的稳定性至关重要。在此，我们报道了周期色氨酸蛋白1(PWP1)参与调节端粒长度的动态平衡。Pwp1似乎对小鼠发育和胚胎干细胞(ESC)存活是必不可少的，因为Pwp1基因敲除的纯合子小鼠和ESCs从未获得过。杂合Pwp1基因敲除小鼠的端粒较短，生殖能力下降。Pwp1缺失导致端粒迅速缩短，并伴随着保护素复合体的减少和端粒区DNA损伤的增加。在机制上，PWP1通过其WD40结构域结合和稳定H4K20me3的保护素复合体，并调节H4K20me3的总水平。PWP1过表达对Pwp1缺陷细胞端粒长度的挽救依赖于SUV4-20H2的共表达和H4K20me3的增加。因此，我们的研究揭示了一种新的蛋白质，在小鼠和人类细胞中都参与了端粒稳态。这些知识将提高我们对染色质结构和组蛋白修饰如何参与维持端粒完整性的理解。
Telomere maintenance is critical for chromosome stability. Here we report that periodic tryptophan protein 1 (PWP1) is involved in regulating telomere length homeostasis. Pwp1 appears to be essential for mouse development and embryonic stem cell (ESC) survival, as homozygous Pwp1-knockout mice and ESCs have never been obtained. Heterozygous Pwp1-knockout mice had shorter telomeres and decreased reproductive capacity. Pwp1 depletion induced rapid telomere shortening accompanied by reduced shelterin complex and increased DNA damage in telomeric regions. Mechanistically, PWP1 bound and stabilized the shelterin complex via its WD40 domains and regulated the overall level of H4K20me3. The rescue of telomere length in Pwp1-deficient cells by PWP1 overexpression depended on SUV4-20H2 co-expression and increased H4K20me3. Therefore, our study revealed a novel protein involved in telomere homeostasis in both mouse and human cells. This knowledge will improve our understanding of how chromatin structure and histone modifications are involved in maintaining telomere integrity.