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UHRF1 通过催化 EG5 多泛素化促进纺锤体组装和染色体聚缩。

UHRF1 promotes spindle assembly and chromosome congression by catalyzing EG5 polyubiquitination.

机构信息

Department of Oncology, Center for Molecular Medicine, Xiangya Hospital, Central South University, Changsha, China.

Hunan Key Laboratory of Molecular Radiation Oncology, Xiangya Hospital, Central South University, Changsha, China.

出版信息

J Cell Biol. 2023 Nov 6;222(11). doi: 10.1083/jcb.202210093. Epub 2023 Sep 20.

DOI:10.1083/jcb.202210093
PMID:37728657
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10510743/
Abstract

UHRF1 is an epigenetic coordinator bridging DNA methylation and histone modifications. Additionally, UHRF1 regulates DNA replication and cell cycle, and its deletion induces G1/S or G2/M cell cycle arrest. The roles of UHRF1 in the regulation of G2/M transition remain poorly understood. UHRF1 depletion caused chromosome misalignment, thereby inducing cell cycle arrest at mitotic metaphase, and these cells exhibited the defects of spindle geometry, prominently manifested as shorter spindles. Mechanistically, UHRF1 protein directly interacts with EG5, a kinesin motor protein, during mitosis. Furthermore, UHRF1 induced EG5 polyubiquitination at the site of K1034 and further promoted the interaction of EG5 with spindle assembly factor TPX2, thereby ensuring accurate EG5 distribution to the spindles during metaphase. Our study clarifies a novel UHRF1 function as a nuclear protein catalyzing EG5 polyubiquitination for proper spindle architecture and faithful genomic transmission, which is independent of its roles in epigenetic regulation and DNA damage repair inside the nucleus. These findings revealed a previously unknown mechanism of UHRF1 in controlling mitotic spindle architecture and chromosome behavior and provided mechanistic evidence for UHRF1 deletion-mediated G2/M arrest.

摘要

UHRF1 是一种表观遗传协调因子，连接 DNA 甲基化和组蛋白修饰。此外，UHRF1 还调节 DNA 复制和细胞周期，其缺失会诱导 G1/S 或 G2/M 细胞周期停滞。UHRF1 在调节 G2/M 转换中的作用仍知之甚少。UHRF1 的耗竭导致染色体排列不齐，从而诱导有丝分裂中期的细胞周期停滞，这些细胞表现出纺锤体几何形状的缺陷，突出表现为纺锤体变短。在机制上，UHRF1 蛋白在有丝分裂期间与驱动蛋白 EG5 直接相互作用。此外，UHRF1 在 K1034 位点诱导 EG5 多泛素化，并进一步促进 EG5 与纺锤体组装因子 TPX2 的相互作用，从而确保 EG5 在中期准确分配到纺锤体上。我们的研究阐明了 UHRF1 的一个新功能，即作为一种核蛋白，催化 EG5 多泛素化，以维持正确的纺锤体结构和忠实的基因组传递，这与它在核内的表观遗传调控和 DNA 损伤修复中的作用无关。这些发现揭示了 UHRF1 控制有丝分裂纺锤体结构和染色体行为的一个以前未知的机制，并为 UHRF1 缺失介导的 G2/M 期阻滞提供了机制证据。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4290/10510743/7f92583a826c/JCB_202210093_Fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4290/10510743/6f99a238fb36/JCB_202210093_Fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4290/10510743/7032bcf50e19/JCB_202210093_FigS1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4290/10510743/35b0e9490418/JCB_202210093_Fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4290/10510743/667042ff9246/JCB_202210093_Fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4290/10510743/1c4949cfa107/JCB_202210093_Fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4290/10510743/e086556d4989/JCB_202210093_FigS2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4290/10510743/3e2db1ddf337/JCB_202210093_Fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4290/10510743/402771a87dbb/JCB_202210093_FigS3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4290/10510743/90863bb37508/JCB_202210093_Fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4290/10510743/7f92583a826c/JCB_202210093_Fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4290/10510743/6f99a238fb36/JCB_202210093_Fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4290/10510743/7032bcf50e19/JCB_202210093_FigS1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4290/10510743/35b0e9490418/JCB_202210093_Fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4290/10510743/667042ff9246/JCB_202210093_Fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4290/10510743/1c4949cfa107/JCB_202210093_Fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4290/10510743/e086556d4989/JCB_202210093_FigS2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4290/10510743/3e2db1ddf337/JCB_202210093_Fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4290/10510743/402771a87dbb/JCB_202210093_FigS3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4290/10510743/90863bb37508/JCB_202210093_Fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4290/10510743/7f92583a826c/JCB_202210093_Fig7.jpg

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