Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo 1088639, Japan.
Nat Commun. 2012 Feb 14;3:676. doi: 10.1038/ncomms1676.
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.
组蛋白蛋白会响应各种外部信号而发生修饰；然而，其机制仍未完全阐明。瓜氨酸化是一种转录后修饰，可将蛋白质中的精氨酸转化为瓜氨酸。在这里，我们通过 p53-PADI4 途径展示了体内和体外 DNA 损伤诱导的组蛋白 H4 的精氨酸 3 位（cit-H4R3）和核纤层蛋白 C 的瓜氨酸化。我们还发现 DNA 损伤诱导的核纤层蛋白 C 的瓜氨酸化。cit-H4R3 和瓜氨酸化的核纤层蛋白 C 在凋亡细胞的碎片化核周围定位。PADI4 的异位表达导致染色质解凝聚并促进 DNA 切割，而 Padi4(-/-) 小鼠则表现出对胸腺中辐射诱导的细胞凋亡的抗性。此外，cit-H4R3 的水平与非小细胞肺癌组织中的 p53 蛋白表达和肿瘤大小呈负相关。我们的研究结果表明，cit-H4R3 可能是一种“凋亡组蛋白密码”，可用于检测受损细胞并诱导核碎片化，这在致癌作用中具有关键作用。
