title: Regulation of histone modification and chromatin structure by the p53-PADI4 pathway.
abstract: 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.
authors.affiliation: Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo 1088639, Japan.
authors.forename: Chizu
authors.initials: C
authors.lastname: Tanikawa
authors.forename: Martha
authors.initials: M
authors.lastname: Espinosa
authors.forename: Akari
authors.initials: A
authors.lastname: Suzuki
authors.forename: Ken
authors.initials: K
authors.lastname: Masuda
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Yamamoto
authors.forename: Eiju
authors.initials: E
authors.lastname: Tsuchiya
authors.forename: Koji
authors.initials: K
authors.lastname: Ueda
authors.forename: Yataro
authors.initials: Y
authors.lastname: Daigo
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Nakamura
authors.forename: Koichi
authors.initials: K
authors.lastname: Matsuda
mesh_terms: D000818:Animals; D017209:Apoptosis; D001120:Arginine / Q000737:chemistry; D002467:Cell Nucleus / Q000378:metabolism; D002843:Chromatin / Q000737:chemistry* / Q000378:metabolism; D002956:Citrulline / Q000737:chemistry; D004247:DNA / Q000737:chemistry; D004249:DNA Damage; D005786:Gene Expression Regulation; D006657:Histones / Q000737:chemistry*; D006801:Humans; D006867:Hydrolases / Q000378:metabolism*; D034904:Lamin Type A / Q000737:chemistry; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D017434:Protein Structure, Tertiary; D000080002:Protein-Arginine Deiminase Type 4; D000076342:Protein-Arginine Deiminases; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D002843:Chromatin; D006657:Histones; D034904:Lamin Type A; D016159:Tumor Suppressor Protein p53; C440308:lamin C; D002956:Citrulline; D004247:DNA; D001120:Arginine; D006867:Hydrolases; C000629235:PADI4 protein, human; D000080002:Protein-Arginine Deiminase Type 4; D000076342:Protein-Arginine Deiminases; C552151:peptidylarginine deiminase 4, mouse