Instituto de Fisiología, Biología Molecular y Neurociencias-Consejo Nacional de Investigaciones Científicas y Técnicas; Departamento de Fisiología, Biología Molecular y Celular, Facultad de Ciencias Exactas y Naturales-Universidad de Buenos Aires, Ciudad Universitaria, Pabellón II, Buenos Aires (C1428EHA), Argentina.
J Biol Chem. 2012 Aug 31;287(36):30789-99. doi: 10.1074/jbc.M112.390120. Epub 2012 Jul 23.
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.
异质核核糖核蛋白（hnRNP）K 是一种核质穿梭蛋白，是 p53 触发的 DNA 损伤反应中的关键因子，作为 p53 对 DNA 损伤反应的辅助因子。hnRNP K 是泛素 E3 连接酶 MDM2 的底物，并且在 DNA 损伤时，其发生去泛素化。与其他翻译后修饰的作用和后果形成鲜明对比的是，hnRNP K 中 SUMO 连接在其 KH3 结构域中的赖氨酸 422 上的作用在 p53 转录共激活中一无所知。在本工作中，我们表明 hnRNP K 在其 KH3 结构域中的赖氨酸 422 处被 SUMO 修饰，并且 SUMO 化受 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 的 SUMO 化，并且这种修饰对于 p53 转录激活是必需的。hnRNP K SUMO 化的缺失会导致 p53 靶基因 p21 的异常调节。我们的发现将 DNA 损伤诱导的 Pc2 激活与通过 hnRNP K SUMO 化的 p53 转录共激活联系起来。
