DNA Damage-induced Heterogeneous Nuclear Ribonucleoprotein K SUMOylation Regulates p53 Transcriptional Activation
DNA Damage-induced Heterogeneous Nuclear Ribonucleoprotein K SUMOylation Regulates p53 Transcriptional Activation
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DOI：
10.1074/jbc.m112.390120
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发表时间：
2012-08-31
影响因子：
4.8
通讯作者：
Srebrow, Anabella
中科院分区：
文献类型：
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作者：
Pelisch, Federico;Pozzi, Berta;Srebrow, Anabella
异质核核糖核蛋白 (hnRNP) K 是一种核质穿梭蛋白，在 p53 触发的 DNA 损伤反应中发挥关键作用，作为 p53 响应 DNA 损伤的辅助因子。 hnRNP K 是泛素 E3 连接酶 MDM2 的底物，在 DNA 损伤后会去泛素化。与其他翻译后修饰的作用和后果形成鲜明对比的是，我们对 SUMO 与 hnRNP K 缀合在 p53 转录共激活中的作用一无所知。在本研究中，我们发现 hnRNP K 在其 KH3 结构域内的第 422 位赖氨酸中被 SUMO 修饰，并且 sumoylation 受 E3 连接酶 Pc2/CBX4 调节。最有趣的是，DNA 损伤通过 Pc2 E3 活性刺激 hnRNP K sumoylation，而这种修饰是 p53 转录激活所必需的。 hnRNP K sumoylation 的废除会导致 p53 靶基因 p21 的异常调节。我们的研究结果通过 hnRNP K sumoylation 将 DNA 损伤诱导的 Pc2 激活与 p53 转录共激活联系起来。
Heterogeneous nuclear ribonucleoprotein (hnRNP) K is a nucleocytoplasmic shuttling protein that is a key player in the p53-triggered DNA damage response, acting as a cofactor for p53 in response to DNA damage. hnRNP K is a substrate of the ubiquitin E3 ligase MDM2 and, upon DNA damage, is de-ubiquitylated. In sharp contrast with the role and consequences of the other post-translational modifications, nothing is known about the role of SUMO conjugation to hnRNP K in p53 transcriptional co-activation. In the present work, we show that hnRNP K is modified by SUMO in lysine 422 within its KH3 domain, and sumoylation is regulated by the E3 ligase Pc2/CBX4. Most interestingly, DNA damage stimulates hnRNP K sumoylation through Pc2 E3 activity, and this modification is required for p53 transcriptional activation. Abrogation of hnRNP K sumoylation leads to an aberrant regulation of the p53 target gene p21. Our findings link the DNA damage-induced Pc2 activation to the p53 transcriptional co-activation through hnRNP K sumoylation.