The UFM1 cascade times mitosis entry associated with microcephaly
The UFM1 cascade times mitosis entry associated with microcephaly
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UFM1级联与小头畸形相关的有丝分裂进入时间
DOI：
10.1096/fj.201901751r
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发表时间：
2020
期刊：
影响因子：
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通讯作者：
Duan Ranhui
中科院分区：
文献类型：
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作者：
Yu Li;Li Guangxu;Deng Jing;Jiang Xuan;Xue Jin;Zhu Yingbao;Huang Wen;Tang Beisha;Duan Ranhui
翻译后修饰通过修饰底物来增强蛋白质组的功能多样性。UFM 1级联是一种新的泛素样修饰系统。UFM 1的突变，其E1（UBA 5）和E2（UFC 1），已被确定在小头畸形患者。然而，其病理机制仍不清楚。在此，我们观察到果蝇成神经细胞（NB）中UFM 1级联的破坏减少了NB的数量，导致大脑体积变小。NB中缺乏ufmylation导致有丝分裂指数增加和G2/M期延长，表明有丝分裂进展缺陷。此外，胚胎的实时成像显示E3连接酶（Ufl 1）功能受损，导致过早进入有丝分裂和细胞化失败。更糟糕的是，胚胎死亡早在Ufm 1缺失后的最初几个有丝分裂周期内就发生了。Ufm 1敲除的胚胎表现出严重的表型，包括中心体脱落、微管缺陷和DNA桥。此外，我们观察到UFM 1级联可以改变CDK 1（pY 15-CDK 1）的酪氨酸-15磷酸化水平，这是G2至M转变的负调节因子。这些发现产生了明确的证据，表明UFM 1级联是一种引起小头畸形的因子，在有丝分裂期进入时调节细胞周期的进展。
Posttranslational modifications enhance the functional diversity of the proteome by modifying the substrates. The UFM1 cascade is a novel ubiquitin‐like modification system. The mutations inUFM1, its E1 (UBA5) and E2 (UFC1), have been identified in patients with microcephaly. However, its pathological mechanisms remain unclear. Herein, we observed the disruption of the UFM1 cascade inDrosophilaneuroblasts (NBs) decreased the number of NBs, leading to a smaller brain size. The lack of ufmylation in NBs resulted in an increased mitotic index and an extended G2/M phase, indicating a defect in mitotic progression. In addition, live imaging of the embryos revealed an impaired E3 ligase (Ufl1) function resulted in premature entry into mitosis and failed cellularization. Even worse, the embryonic lethality occurred as early as within the first few mitotic cycles following the depletion ofUfm1.Knockdown of ufmylation in the fixed embryos exhibited severe phenotypes, including detached centrosomes, defective microtubules, and DNA bridge. Furthermore, we observed that the UFM1 cascade could alter the level of phosphorylation on tyrosine‐15 of CDK1 (pY15‐CDK1), which is a negative regulator of the G2 to M transition. These findings yield unambiguous evidence suggesting that the UFM1 cascade is a microcephaly‐causing factor that regulates the progression of the cell cycle at mitosis phase entry.