The ATM-E6AP-MASTL axis mediates DNA damage checkpoint recovery.
The ATM-E6AP-MASTL axis mediates DNA damage checkpoint recovery.
复制标题
ATM-E6AP-MASTL 轴介导 DNA 损伤检查点恢复。
DOI：
10.1101/2023.02.22.529521
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Peng,Aimin
中科院分区：
文献类型：
--
作者：
Li,Yanqiu;Wang,Feifei;Li,Xin;Wang,Ling;Yang,Zheng;You,Zhongsheng;Peng,Aimin
DNA损伤后的检查点激活通过抑制细胞周期蛋白依赖性激酶（CDK）引起短暂的细胞周期停滞。然而，在DNA损伤后细胞周期恢复如何启动在很大程度上仍然是难以捉摸的。在这项研究中，我们发现MASTL激酶的蛋白水平上调后数小时DNA损伤。MASTL通过阻止PP 2A/B55催化的CDK底物去磷酸化来促进细胞周期进程。DNA损伤诱导的MASTL上调是由蛋白质降解减少引起的，并且在有丝分裂激酶中是独特的。我们鉴定E6 AP为介导MASTL降解的E3泛素连接酶。MASTL的降解受到抑制后，DNA损伤的结果，从MASTL的E6 AP的解离。E6 AP缺失减少了DNA损伤信号传导，并以MASTL依赖的方式促进细胞周期从DNA损伤检查点恢复。此外，我们发现，E6 AP在Ser-218处被ATM磷酸化，并且这种磷酸化是其从MASTL中解离、MASTL的稳定和细胞周期进程的及时恢复所必需的。总之，我们的数据显示，ATM/ATR依赖性信号在激活DNA损伤检查点的同时，也启动了细胞周期从停滞中恢复。因此，这导致了一种类似计时器的机制，确保了DNA损伤检查点的瞬时性质。
Checkpoint activation after DNA damage causes a transient cell cycle arrest by suppressing cyclin-dependent kinases (CDKs). However, it remains largely elusive how cell cycle recovery is initiated after DNA damage. In this study, we discovered the upregulated protein level of MASTL kinase hours after DNA damage. MASTL promotes cell cycle progression by preventing PP2A/B55-catalyzed dephosphorylation of CDK substrates. DNA damage-induced MASTL upregulation was caused by decreased protein degradation, and was unique among mitotic kinases. We identified E6AP as the E3 ubiquitin ligase that mediated MASTL degradation. MASTL degradation was inhibited upon DNA damage as a result of the dissociation of E6AP from MASTL. E6AP depletion reduced DNA damage signaling, and promoted cell cycle recovery from the DNA damage checkpoint, in a MASTL-dependent manner. Furthermore, we found that E6AP was phosphorylated at Ser-218 by ATM after DNA damage and that this phosphorylation was required for its dissociation from MASTL, the stabilization of MASTL, and the timely recovery of cell cycle progression. Together, our data revealed that ATM/ATR-dependent signaling, while activating the DNA damage checkpoint, also initiates cell cycle recovery from the arrest. Consequently, this results in a timer-like mechanism that ensures the transient nature of the DNA damage checkpoint.
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DOI：
10.1159/000130970
发表时间：
1978-01-01
期刊：
CYTOGENETICS AND CELL GENETICS
影响因子：
--
作者：
CHANDLER, ME;YUNIS, JJ
通讯作者：
YUNIS, JJ
人类白血病细胞系 HL-60 中的癌基因迁移率。
影响因子：
--
作者：
Wolman,SR;Lanfrancone,L;Dalla-Favera,R;Ripley,S;Henderson,AS
通讯作者：
Henderson,AS
影响因子：
64.8
作者：
COLLINS, S;GROUDINE, M
通讯作者：
GROUDINE, M
基因扩增、耐药性和癌症。
影响因子：
11.2
作者：
Schimke,RT
通讯作者：
Schimke,RT
DOI：
10.1073/pnas.83.9.2984
发表时间：
1986-05-01
影响因子：
11.1
作者：
PELICCI, PG;KNOWLES, DM;DALLAFAVERA, R
通讯作者：
DALLAFAVERA, R