eIF3a-PPP2R5A-mediated ATM/ATR dephosphorylation is essential for irinotecan-induced DNA damage response.
eIF3a-PPP2R5A-mediated ATM/ATR dephosphorylation is essential for irinotecan-induced DNA damage response.
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eIF3a —PPP2R5A — 介导的 ATM/ATR 去磷酸化对于伊立替康 — 诱导的 DNA 损伤反应至关重要
DOI：
10.1111/cpr.13208
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发表时间：
2022-04
影响因子：
8.5
通讯作者：
Liu, Zhao-Qian
中科院分区：
文献类型：
--
作者：
Mei, Chao;Sun, Ze-En;Tan, Li-Ming;Gong, Jian-Ping;Li, Xi;Liu, Zhao-Qian
个体的差异和普遍性的抗性阻碍了基于虹膜的治疗有效性的优化。
CCK8细胞活力和克隆存活分析用于测试EIF3A在HT29中的虹膜敏感性的调节作用，并且通过在体外验证了CACO2细胞线的体外作用，还通过对细胞诱导的irinotafter sancore sancop profter cyerty profter cyerty profter cy ternity bercopt bercopt bervivo验证。测定。进行了co-IP，荧光素酶报道测定法，RIP和流式细胞仪分析以研究下划线机理。
我们证明，EIF3A通过翻译抑制PPP2R5A（一种磷酸化酶，在DNA修复后直接脱磷酸化并灭活ATM/ATR，从而使PPP2R5A抑制完整会导致ATM/ATR失活，从而激活ATM/ATR信号。
我们的研究表明，EIF3A具有很高的影响表型功能的潜力，这可能对易感人士的早期鉴定以及向伊立替康治疗的患者提供个性化药物的早期贡献。
EIF3A的示意图调节虹膜的敏感性，包括Irinotecan的衍生物及其衍生物，迅速诱导SSBS在恶性细胞中转换为DSB。 TR信号顺序激活下游控制一系列的DNA损伤响应，例如细胞循环疗法，DNA修复和凋亡信号，一旦修复过程完成，包括PPP2R5A在内甲基化和激活，导致DNA损伤修复和细胞死亡受损。
The individual differences and pervasive resistance seriously hinder the optimization of irinotecan‐based therapeutic effectiveness. Eukaryotic translation initiation factor 3a (eIF3a) plays a key role in tumour occurrence, prognosis and therapeutic response. This study focused on the role of eIF3a in irinotecan‐induced DNA damage response. The cck8 cell viability and clone survival analyses were used to test the regulatory role of eIF3a on irinotecan sensitivity in HT29 and CACO2 cell lines in vitro. This regulatory role was also verified in vivo by conducting subcutaneous xenograft model. Irinotecan‐induced DNA damage, cell cycle arrest and apoptosis were tested by flow cytometry analysis, TUNEL staining, western blot and comet assays. The immunofluorescence, co‐IP, luciferase reporter assay, RIP and flow cytometric analyses were carried out to investigate the underline mechanism. We demonstrated that eIF3a continuously activates ATM/ATR signal by translationally inhibiting PPP2R5A, a phosphatase that directly dephosphorylates and inactivates ATM/ATR after DNA repair complete. Suppression of PPP2R5A resulted in chronic ATM/ATR phosphorylation and activation, impairing DNA repair and enhancing irinotecan sensitivity. Our study suggested eIF3a with a high potential to influence phenotypic functions, which may contribute substantially to the early identification of susceptible individuals and the provision of personalized medication to irinotecan‐treated patients. Schematic diagram for eIF3a regulates the sensitivity of irinotecan. Left, camptothecin and its derivatives, including irinotecan, rapidly induce SSBs in malignant cells. The SSBs would convert into DSBs when encountering the replicating forks. The existence of DNA lesions rapidly trigged DNA damage response, which was initiated by autophosphorylation of ATM and ATR. The activation of ATM/ATR signal sequentially activates the downstream effectors to control a series of DNA damage response like cell cycler arrest, DNA repair and apoptosis signal. Right, once the repair process finished, specific protein phosphatases including PPP2R5A are involved in the dephosphorylation of p‐ATM and p‐ATR so as to promote checkpoint recovery. eIF3a participates in this process by translationally regulating PPP2R5A. Suppression of PPP2R5A induces persistent ATM and ATR phosphorylation and activation, leading to impaired DNA damage repair and cell death.
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DOI：
10.1016/j.apsb.2018.07.008
发表时间：
2018-10
期刊：
Acta pharmaceutica Sinica. B
影响因子：
--
作者：
Hevener K;Verstak TA;Lutat KE;Riggsbee DL;Mooney JW
通讯作者：
Mooney JW
DOI：
10.1111/febs.13573
发表时间：
2016-03
期刊：
The FEBS journal
影响因子：
--
作者：
Sangodkar J;Farrington CC;McClinch K;Galsky MD;Kastrinsky DB;Narla G
通讯作者：
Narla G
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
eIF3a通过调节DSB DNA修复对蒽环类化疗耐药的影响
影响因子：
5.8
作者：
Chen, Juan;Liu, Jun-Yan;Yin, Ji-Ye
通讯作者：
Yin, Ji-Ye
影响因子：
16
作者：
Pagliuca, Felicia Walton;Collins, Mark O.;Lichawska, Agata;Zegerman, Philip;Choudhary, Jyoti S.;Pines, Jonathon
通讯作者：
Pines, Jonathon