The Institute of Medical Science, The University Of Tokyo

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Regulation of histone modification and chromatin structure by the p53–PADI4 pathway

Nature communications doi: 10.1038/ncomms1676
Chizu Tanikawa, Martha Espinosa, Akari Suzuki, Ken Masuda, Kazuhiko Yamamoto, Eiju Tsuchiya, Koji Ueda, Yataro Daigo, Yusuke Nakamura & Koichi Matsuda

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.