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极光 B 特异性开关对于在中期/后期过渡时防止非分离是必需的。

The Aurora B specificity switch is required to protect from non-disjunction at the metaphase/anaphase transition.

机构信息

Protein Phosphorylation Laboratory, Francis Crick Institute, 1 Midland Rd, London, NW1 1AT, UK.

Cancer Research UK, Manchester Institute, Alderley Park, SK10 4TG, UK.

出版信息

Nat Commun. 2020 Mar 13;11(1):1396. doi: 10.1038/s41467-020-15163-6.

DOI:10.1038/s41467-020-15163-6
PMID:32170202
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7070073/
Abstract

The Aurora B abscission checkpoint delays cytokinesis until resolution of DNA trapped in the cleavage furrow. This process involves PKCε phosphorylation of Aurora B S227. Assessing if this PKCε-Aurora B module provides a more widely exploited genome-protective control for the cell cycle, we show Aurora B phosphorylation at S227 by PKCε also occurs during mitosis. Expression of Aurora B S227A phenocopies inhibition of PKCε in by-passing the delay and resolution at anaphase entry that is associated with non-disjunction and catenation of sister chromatids. Implementation of this anaphase delay is reflected in PKCε activation following cell cycle dependent cleavage by caspase 7; knock-down of caspase 7 phenocopies PKCε loss, in a manner rescued by ectopically expressing/generating a free PKCε catalytic domain. Molecular dynamics indicates that Aurora B S227 phosphorylation induces conformational changes and this manifests in a profound switch in specificity towards S29 TopoIIα phosphorylation, a response necessary for catenation resolution during mitosis.

摘要

极光 B 脱离检查点延迟胞质分裂，直到解决陷入分裂沟的 DNA。这个过程涉及 PKCε 对 Aurora B S227 的磷酸化。评估这个 PKCε-Aurora B 模块是否为细胞周期提供了更广泛的基因组保护控制，我们发现 PKCε 也在有丝分裂期间使 Aurora B 的 S227 发生磷酸化。Aurora B S227A 的表达模拟了 PKCε 的抑制作用，绕过了与非分离和姐妹染色单体连接相关的后期进入的延迟和解决。这种后期延迟的实现反映在 caspase 7 依赖性细胞周期切割后 PKCε 的激活中；caspase 7 的敲低模拟了 PKCε 的缺失，以异位表达/生成游离 PKCε 催化结构域的方式得到挽救。分子动力学表明，极光 B S227 的磷酸化诱导构象变化，这表现在对 S29 TopoIIα 磷酸化的特异性上发生了深刻的转变，这是有丝分裂过程中连接体分辨率所必需的反应。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6653/7070073/f526cfaf82d0/41467_2020_15163_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6653/7070073/6f736b9ebd23/41467_2020_15163_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6653/7070073/825e7e3b93da/41467_2020_15163_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6653/7070073/96c88982fdd8/41467_2020_15163_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6653/7070073/ea205aed2d88/41467_2020_15163_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6653/7070073/487d674d31b3/41467_2020_15163_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6653/7070073/f526cfaf82d0/41467_2020_15163_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6653/7070073/6f736b9ebd23/41467_2020_15163_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6653/7070073/825e7e3b93da/41467_2020_15163_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6653/7070073/96c88982fdd8/41467_2020_15163_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6653/7070073/ea205aed2d88/41467_2020_15163_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6653/7070073/487d674d31b3/41467_2020_15163_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6653/7070073/f526cfaf82d0/41467_2020_15163_Fig6_HTML.jpg

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