Homeodomain Proteins Directly Regulate ATM Kinase Activity.
Homeodomain Proteins Directly Regulate ATM Kinase Activity.
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同源结构域蛋白直接调节 ATM 激酶活性。
DOI：
10.1016/j.celrep.2018.06.089
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发表时间：
2018
期刊：
影响因子：
8.8
通讯作者：
Paull,TanyaT
中科院分区：
文献类型：
--
作者：
Johnson,TanyaE;Lee,Ji-Hoon;Myler,LoganR;Zhou,Yi;Mosley,TrenellJ;Yang,Soo-Hyun;Bio-BricksforMolecularMachinesFRIStream;Uprety,Nadima;Kim,Jonghwan;Paull,TanyaT
共济失调-毛细血管扩张突变(ATM)是一种丝氨酸/苏氨酸激酶，协调对DNA双链断裂和氧化应激的反应。NKX3.1是一种前列腺特异性转录因子，最近被证明通过其高度保守的同源结构域直接刺激ATM激酶活性。在这里，我们展示了同源结构域家族的其他成员也可以调节ATM激酶的活性。我们发现6个具有代表性的同源结构域蛋白(NKX3.1、NKX2.2、TTF1、NKX2.5、HOXB7和CDX2)与ATM以及与结合DNA双链断裂激活ATM的Mre11-Rad50-Nbs1(MRN)复合体相互作用。同源结构域蛋白与ATM之间的结合在体外刺激氧化诱导的ATM激活，但在MRN和DNA存在的情况下以及在人类细胞中抑制ATM激酶的活性。这些发现表明，许多组织特异性的同源结构域蛋白可能在发育和分化过程中调节ATM的活性，这是控制DNA损伤反应的独特机制。
Ataxia-telangiectasia mutated (ATM) is a serine/threonine kinase that coordinates the response to DNA double-strand breaks and oxidative stress. NKX3.1, a prostate-specific transcription factor, was recently shown to directly stimulate ATM kinase activity through its highly conserved homeodomain. Here, we show that other members of the homeodomain family can also regulate ATM kinase activity. We found that six representative homeodomain proteins (NKX3.1, NKX2.2, TTF1, NKX2.5, HOXB7, and CDX2) physically and functionally interact with ATM and with the Mre11-Rad50-Nbs1 (MRN) complex that activates ATM in combination with DNA double-strand breaks. The binding between homeodomain proteins and ATM stimulates oxidation-induced ATM activationin vitrobut inhibits ATM kinase activity in the presence of MRN and DNA and in human cells. These findings suggest that many tissue-specific homeodomain proteins may regulate ATM activity during development and differentiation and that this is a unique mechanism for the control of the DNA damage response.