Abstract
Abstract Histone proteins are modified in response to various external signals, however their mechanisms are still not fully understood. We here report in vivo and in vitro citrullination of arginine 3 residue of histone H4 (H4R3) in response to DNA damage through the p53-PADI4 pathway. We also observed DNA damage-induced citrullination of lamin C through the p53-PADI4 pathway. Citrullinated H4R3 (cit-H4R3) and citrullinated lamin C are located around fragmented nuclei in apoptotic cells. Ectopic expression of PADI4 led to chromatin decondensation and promoted DNA cleavage, while Padi4-/- mice exhibited resistance to radiation-induced apoptosis in the thymus. We also found loss of function mutations of the PADI4 gene in several cancer cell lines. Furthermore, the level of cit-H4R3 was negatively correlated with that of p53 protein in cancer cells and with tumor size in non-small cell lung cancer tissues. Our findings reveal that citrullination of H4R3 would be an “apoptotic histone code” to detect damaged cells and induce nuclear fragmentation, which plays a crucial role in carcinogenesis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5015. doi:1538-7445.AM2012-5015
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