Ubiquitin-fold modifier 1 (UFM1) is involved in neural and erythroid development, yet its biological roles in these processes are unknown. Here, we generated zebrafish models deficient in Ufm1 and Ufl1 that exhibited telomere shortening associated with developmental delay, impaired hematopoiesis and premature aging. We further report that HeLa cells lacking UFL1 have instability of telomeres replicated by leading-strand synthesis. We uncover that MRE11 UFMylation is necessary for the recruitment of the phosphatase PP1-α leading to dephosphorylation of NBS1. In the absence of UFMylation, NBS1 remains phosphorylated, thereby reducing MRN recruitment to telomeres. The absence of MRN at telomeres favors the formation of the TRF2-Apollo/SNM1 complex consistent with the loss of leading telomeres. These results suggest that MRE11-UFMylation may serve as module to recruit PP1-α. Last, zebrafish expressing Mre11 that cannot be UFMylated phenocopy Ufm1-deficient zebrafish, demonstrating that UFMylation of MRE11 is a previously undescribed evolutionarily conserved mechanisms regulating telomere length.

中文翻译：

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MRE11的UFMylation对端粒长度维持和造血干细胞存活至关重要

泛素折叠修饰剂 1 (UFM1) 参与神经和红系发育，但其在这些过程中的生物学作用尚不清楚。在这里，我们生成了缺乏Ufm1和Ufl1的斑马鱼模型表现出与发育迟缓、造血功能受损和过早衰老相关的端粒缩短。我们进一步报告缺乏 UFL1 的 HeLa 细胞具有通过前链合成复制的端粒的不稳定性。我们发现 MRE11 UFMylation 是募集磷酸酶 PP1-α 导致 NBS1 去磷酸化所必需的。在没有 UFMylation 的情况下，NBS1 保持磷酸化，从而减少 MRN 向端粒的募集。端粒缺乏 MRN 有利于 TRF2-Apollo/SNM1 复合物的形成，这与领先端粒的缺失一致。这些结果表明 MRE11-UFMylation 可以作为招募 PP1-α 的模块。最后，斑马鱼表达不能是 UFMylated phenocopy Ufm1的 Mre11-缺陷斑马鱼，证明 MRE11 的 UFMylation 是一种以前未描述的调节端粒长度的进化保守机制。