Kranz Dominique, Dohmesen Christoph, Dobbelstein Matthias
Medical Biotechnology Center, Institute for Medical Biology, University of Southern Denmark, 5000 Odense C, Denmark.
J Cell Biol. 2008 Jul 14;182(1):197-213. doi: 10.1083/jcb.200712014.
The histone acetyltransferase Tip60 regulates the apoptotic response to ultraviolet (UV) irradiation. A previously suggested mechanism for this regulation consists of the ability of Tip60 to coactivate transcription by the tumor suppressor p53. In this study, we show that Tip60 is required for the early DNA damage response (DDR) to UV, including the phosphorylation of histone 2AX, c-Jun N-terminal kinases (JNKs), and ataxia telangiectasia-related substrates. In contrast, p53 was not required for UV-induced DDR. Rather, p53 accumulation by either knockdown of Mdm2 or addition of an Mdm2 inhibitor, Nutlin-3, before irradiation strongly attenuated the UV-induced DDR and increased cell survival. This protective effect of preaccumulated p53 was mediated, at least in part, by the increased expression of CDKN1A/p21, subsequent down-regulation of BRCA1, and impaired JNK activation accompanied by decreased association of replication protein A with chromatin. We conclude that Tip60 enables UV-induced DDR signaling even in the absence of p53, whereas preaccumulated p53 suppresses UV-induced DDR by reducing the levels of BRCA1.
组蛋白乙酰转移酶Tip60可调节对紫外线（UV）照射的凋亡反应。此前提出的这种调节机制包括Tip60与肿瘤抑制因子p53共同激活转录的能力。在本研究中，我们发现Tip60是UV诱导的早期DNA损伤反应（DDR）所必需的，包括组蛋白2AX、c-Jun氨基末端激酶（JNKs）以及共济失调毛细血管扩张症相关底物的磷酸化。相比之下，UV诱导的DDR并不需要p53。相反，在照射前通过敲低Mdm2或添加Mdm2抑制剂Nutlin-3使p53积累，会强烈减弱UV诱导的DDR并提高细胞存活率。预先积累的p53的这种保护作用至少部分是由CDKN1A/p21表达增加、随后BRCA1下调以及JNK激活受损并伴有复制蛋白A与染色质结合减少介导的。我们得出结论，即使在没有p53的情况下，Tip60也能使UV诱导的DDR信号传导，而预先积累的p53通过降低BRCA1水平来抑制UV诱导的DDR。
