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

Nat Commun. 2012 Feb 14;3:676. doi: 10.1038/ncomms1676.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Arginine / chemistry
  • Cell Nucleus / metabolism
  • Chromatin / chemistry*
  • Chromatin / metabolism
  • Citrulline / chemistry
  • DNA / chemistry
  • DNA Damage
  • Gene Expression Regulation*
  • Histones / chemistry*
  • Humans
  • Hydrolases / metabolism*
  • Lamin Type A / chemistry
  • Mice
  • Mice, Transgenic
  • Models, Biological
  • Protein Structure, Tertiary
  • Protein-Arginine Deiminase Type 4
  • Protein-Arginine Deiminases
  • Tumor Suppressor Protein p53 / metabolism*


  • Chromatin
  • Histones
  • Lamin Type A
  • Tumor Suppressor Protein p53
  • lamin C
  • Citrulline
  • DNA
  • Arginine
  • Hydrolases
  • PADI4 protein, human
  • Protein-Arginine Deiminase Type 4
  • Protein-Arginine Deiminases
  • peptidylarginine deiminase 4, mouse