title: Biphasic reduction of histone H3 phosphorylation in response to N-nitroso compounds induced DNA damage.
abstract: N-nitroso compounds (NOC) can cause cancers in a wide variety of animal species, and many of them are also potential human carcinogens. However, their underlying genotoxic mechanisms occurred within the context of chromatin, such as aberrant histone modifications, remained elusive.
  
  
  
  We investigated the dynamic landscapes of histone modifications after N-nitroso compound N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) and N-methyl-N-nitroso-urea (MNU) exposure. Among the altered histone modifications, we also investigated the control mechanisms of histone H3 phosphorylation changes and its possible implications on transcriptional repression.
  
  
  
  Significantly, we find a specific biphasic reduction of histone H3 phosphorylation at serine 10 (H3S10ph) and serine 28 (H3S28ph), and a rapid decrease of histone H4 acetylation upon MNNG and MNU exposure. Further investigations reveal that the first hypophosphorylation of H3 occurs in a poly(ADP-ribosyl)ation enzyme PARP-1 (Poly(ADP-Ribose) Polymerase 1) dependent manner, whereas the second decline of H3 phosphorylation is at least partially under the control of histone kinase VRK1 (vaccinia-related kinase 1) and dependent on the tumor suppressor protein p53. In addition, DNA damage induced down-regulation of H3S10/S28 phosphorylation also functions in transcriptional repression of genes, such as cell-cycle regulators.
  
  
  
  Alkylating damage induced by NOC elicits a biphasic reduction of histone H3 phosphorylation with distinct control mechanisms, which is contributing to DNA damage responses such as the repair-facilitated transcriptional repression.
  
  
  
  Identification of the dynamic changes and underlying mechanisms of histone modifications upon NOC exposure would be of great help in understanding the epigenetic regulations of NOC induced DNA damage responses.
authors.affiliation: Department of Pathology and Pathophysiology, Research Center for Air Pollution and Health, Key Laboratory of Disease Proteomics of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou 310058, China.
authors.forename: Kailin
authors.initials: K
authors.lastname: Chen
authors.affiliation: Department of Pathology and Pathophysiology, Research Center for Air Pollution and Health, Key Laboratory of Disease Proteomics of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou 310058, China.
authors.forename: Shuilian
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Department of Pathology and Pathophysiology, Research Center for Air Pollution and Health, Key Laboratory of Disease Proteomics of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou 310058, China.
authors.forename: Xinxin
authors.initials: X
authors.lastname: Ke
authors.affiliation: Department of Pathology and Pathophysiology, Research Center for Air Pollution and Health, Key Laboratory of Disease Proteomics of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou 310058, China.
authors.forename: Hongyan
authors.initials: H
authors.lastname: Qi
authors.affiliation: Department of Pathology and Pathophysiology, Research Center for Air Pollution and Health, Key Laboratory of Disease Proteomics of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou 310058, China.
authors.forename: Jimin
authors.initials: J
authors.lastname: Shao
authors.affiliation: Department of Pathology and Pathophysiology, Research Center for Air Pollution and Health, Key Laboratory of Disease Proteomics of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou 310058, China. Electronic address: shenjingwzy@zju.edu.cn.
authors.forename: Jing
authors.initials: J
authors.lastname: Shen
mesh_terms: D000107:Acetylation / Q000187:drug effects; D002460:Cell Line; D045744:Cell Line, Tumor; D002843:Chromatin / Q000187:drug effects; D004249:DNA Damage / Q000187:drug effects*; D015536:Down-Regulation / Q000187:drug effects; D006367:HeLa Cells; D006657:Histones / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008769:Methylnitronitrosoguanidine / Q000494:pharmacology; D008770:Methylnitrosourea / Q000494:pharmacology; D009603:Nitroso Compounds / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D002843:Chromatin; D006657:Histones; D047908:Intracellular Signaling Peptides and Proteins; D009603:Nitroso Compounds; D016159:Tumor Suppressor Protein p53; D008769:Methylnitronitrosoguanidine; D008770:Methylnitrosourea; D011065:Poly(ADP-ribose) Polymerases; D017346:Protein Serine-Threonine Kinases; C109890:VRK1 protein, human
keywords: Chemical carcinogen; DNA damage response; Epigenetics; Histone modifications; N-nitroso compounds