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

Chizu Tanikawa, Martha Espinosa, Akari Suzuki, Ken Masuda, Kazuhiko Yamamoto, Eiju Tsuchiya, Koji Ueda, Yataro Daigo, Yusuke Nakamura, Koichi Matsuda

Nature communications 2012 Feb 14

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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.

Citation

Chizu Tanikawa, Martha Espinosa, Akari Suzuki, Ken Masuda, Kazuhiko Yamamoto, Eiju Tsuchiya, Koji Ueda, Yataro Daigo, Yusuke Nakamura, Koichi Matsuda. Regulation of histone modification and chromatin structure by the p53-PADI4 pathway. Nature communications. 2012 Feb 14;3:676