Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX 78712, USA; Howard Hughes Medical Institute, The University of Texas at Austin, Austin, TX 78712, USA.
Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX 78712, USA.
Cell Rep. 2018 Aug 7;24(6):1471-1483. doi: 10.1016/j.celrep.2018.06.089.
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 activation in vitro but 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.
共济失调毛细血管扩张突变基因（ATM）是一种丝氨酸/苏氨酸激酶，它协调细胞对 DNA 双链断裂和氧化应激的反应。最近有研究表明，NKX3.1 是一种前列腺特异性转录因子，其高度保守的同源结构域可直接刺激 ATM 激酶活性。在这里，我们发现其他同源结构域家族的成员也可以调节 ATM 激酶活性。我们发现，六个代表性的同源结构域蛋白（NKX3.1、NKX2.2、TTF1、NKX2.5、HOXB7 和 CDX2）与 ATM 以及激活 ATM 的 Mre11-Rad50-Nbs1（MRN）复合物在物理和功能上相互作用，与 DNA 双链断裂相结合。同源结构域蛋白与 ATM 的结合在体外刺激氧化诱导的 ATM 激活，但在存在 MRN 和 DNA 的情况下以及在人细胞中抑制 ATM 激酶活性。这些发现表明，许多组织特异性同源结构域蛋白可能在发育和分化过程中调节 ATM 活性，这是控制 DNA 损伤反应的一种独特机制。
