Regulation of histone modification and chromatin structure by the p53-PADI4 pathway
Regulation of histone modification and chromatin structure by the p53-PADI4 pathway
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DOI：
10.1038/ncomms1676
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发表时间：
2012-02-01
影响因子：
16.6
通讯作者：
Matsuda, Koichi
中科院分区：
文献类型：
--
作者：
Tanikawa, Chizu;Espinosa, Martha;Matsuda, Koichi
组蛋白会响应各种外部信号而发生修饰;然而，其机制仍不完全清楚。瓜氨酸是一种转录后修饰，可将蛋白质中的精氨酸转化为瓜氨酸。在这里，我们显示了体内和体外组蛋白H4的精氨酸3残基的瓜氨酸（cit-H4 R3）通过p53-PADI 4途径对DNA损伤的反应。我们还显示了DNA损伤诱导的核纤层蛋白C的瓜氨酸。Cit-H4 R3和瓜氨酸化核纤层蛋白C定位于凋亡细胞中碎裂的细胞核周围。Padi 4的异位表达导致染色质去凝聚并促进DNA切割，而Padi 4（-/-）小鼠在胸腺中表现出对辐射诱导的细胞凋亡的抗性。此外，cit-H4 R3的水平与p53蛋白表达和非小细胞肺癌组织中的肿瘤大小呈负相关。我们的研究结果表明，cit-H4 R3可能是一个“凋亡组蛋白密码”，以检测受损细胞和诱导核碎裂，这在癌变中具有至关重要的作用。
Histone proteins are modified in response to various external signals; however, their mechanisms are still not fully understood. Citrullination is a post-transcriptional modification that converts arginine in proteins into citrulline. Here we show in vivo and in vitro citrullination of the arginine 3 residue of histone H4 (cit-H4R3) in response to DNA damage through the p53-PADI4 pathway. We also show DNA damage-induced citrullination of Lamin C. Cit-H4R3 and citrullinated Lamin C localize around fragmented nuclei in apoptotic cells. Ectopic expression of PADI4 leads to chromatin decondensation and promotes DNA cleavage, whereas Padi4(-/-) mice exhibit resistance to radiation-induced apoptosis in the thymus. Furthermore, the level of cit-H4R3 is negatively correlated with p53 protein expression and with tumour size in non-small cell lung cancer tissues. Our findings reveal that cit-H4R3 may be an 'apoptotic histone code' to detect damaged cells and induce nuclear fragmentation, which has a crucial role in carcinogenesis.