Histone proteins are modified in response to various external signals; however, their mechanismsare still not fully understood. Citrullination is a post-transcriptional modification that convertsarginine in proteins into citrulline. Here we show in vivo and in vitro citrullination of the arginine 3residue 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 citrullinatedLamin C localize around fragmented nuclei in apoptotic cells. Ectopic expression of PADI4 leadsto chromatin decondensation and promotes DnA cleavage, whereas Padi4/ mice exhibitresistance to radiation-induced apoptosis in the thymus. Furthermore, the level of cit-H4R3 isnegatively correlated with p53 protein expression and with tumour size in non-small cell lungcancer tissues. our findings reveal that cit-H4R3 may be an ‘apoptotic histone code’ to detectdamaged cells and induce nuclear fragmentation, which has a crucial role in carcinogenesis.
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