Dual-functional significance of ATM-mediated phosphorylation of spindle assembly checkpoint component Bub3 in mitosis and the DNA damage response.
Dual-functional significance of ATM-mediated phosphorylation of spindle assembly checkpoint component Bub3 in mitosis and the DNA damage response.
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DOI：
10.1016/j.jbc.2022.101632
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发表时间：
2022-03
期刊：
影响因子：
--
通讯作者：
Xu B
中科院分区：
文献类型：
--
作者：
Xiao M;Zhang S;Liu Z;Mo Y;Wang H;Zhao X;Yang X;Boohaker RJ;Chen Y;Han Y;Liu H;Xu B
DNA损伤反应（DDR）和有丝分裂检查点对维持基因组稳定性至关重要。在参与这些过程的蛋白质中，共济失调-毛细血管扩张突变（ATM）激酶是DDR和纺锤体组装检查点（SAC）激活所必需的。在没有DNA损伤的有丝分裂中，ATM的酶活性增强;然而，ATM在有丝分裂中的底物是未知的。利用稳定同位素标记的氨基酸在细胞培养质谱分析，我们确定了一些蛋白质，可以潜在地被ATM在有丝分裂过程中磷酸化。该列表高度富集参与细胞周期调节和DDR的蛋白质。其中，我们进一步验证了ATM在体外和体内对丝氨酸135（Ser 135）的磷酸化芽生不受SAC主要成分苯并咪唑3（Bub 3）的抑制。在有丝分裂过程中，这种磷酸化促进了另一种SAC组分苯并咪唑1的活化。Bub 3 Ser 135突变为丙氨酸导致SAC活化缺陷。此外，我们发现ATM介导的Bub 3在Ser 135上的磷酸化也被电离辐射诱导的DNA损伤所诱导。然而，这一事件导致独立的信号转导，涉及与Ku 70-Ku 80-DNA-PKcs传感器/激酶复合物的相互作用，导致有效的非同源末端连接修复。两者合计，我们强调了通过ATM磷酸化的Bub 3 Ser 135的kinetochorse导向的信号和双链断裂修复途径之间的串扰的功能意义。
Both the DNA damage response (DDR) and the mitotic checkpoint are critical for the maintenance of genomic stability. Among proteins involved in these processes, the ataxia–telangiectasia mutated (ATM) kinase is required for both activation of the DDR and the spindle assembly checkpoint (SAC). In mitosis without DNA damage, the enzymatic activity of ATM is enhanced; however, substrates of ATM in mitosis are unknown. Using stable isotope labeling of amino acids in cell culture mass spectrometry analysis, we identified a number of proteins that can potentially be phosphorylated by ATM during mitosis. This list is highly enriched in proteins involved in cell cycle regulation and the DDR. Among them, we further validated that ATM phosphorylated budding uninhibited by benzimidazoles 3 (Bub3), a major component of the SAC, on serine 135 (Ser135) both in vitro and in vivo. During mitosis, this phosphorylation promoted activation of another SAC component, benzimidazoles 1. Mutation of Bub3 Ser135 to alanine led to a defect in SAC activation. Furthermore, we found that ATM-mediated phosphorylation of Bub3 on Ser135 was also induced by ionizing radiation-induced DNA damage. However, this event resulted in independent signaling involving interaction with the Ku70–Ku80–DNA-PKcs sensor/kinase complex, leading to efficient nonhomologous end-joining repair. Taken together, we highlight the functional significance of the crosstalk between the kinetochore-oriented signal and double-strand break repair pathways via ATM phosphorylation of Bub3 on Ser135.
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影响因子：
64.8
作者：
Alfieri, Claudio;Chang, Leifu;Zhang, Ziguo;Yang, Jing;Maslen, Sarah;Skehel, Mark;Barford, David
通讯作者：
Barford, David
DOI：
10.1038/s41571-018-0114-z
发表时间：
2019-03
期刊：
Nature reviews. Clinical oncology
影响因子：
--
作者：
Pilié PG;Tang C;Mills GB;Yap TA
通讯作者：
Yap TA
影响因子：
56.9
作者：
Lee, JH;Paull, TT
通讯作者：
Paull, TT
影响因子：
11.2
作者：
Liu, Changlong;Banister, Carolyn E.;Buckhaults, Phillip J.
通讯作者：
Buckhaults, Phillip J.
影响因子：
1.4
作者：
Morales, Andressa Gois;Pezuk, Julia Alejandra;Tone, Luiz Gonzaga
通讯作者：
Tone, Luiz Gonzaga