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Biphasic reduction of histone H3 phosphorylation in response to N-nitroso compounds induced DNA damage

Kailin Chen1, Shuilian Zhang1, Xinxin Ke1

  • 1Department 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.

Biochimica Et Biophysica Acta
|May 29, 2016
PubMed
Abstract

Insights

N-nitroso compounds (NOC) cause cancer via genotoxic mechanisms. This study reveals NOC exposure induces biphasic reductions in histone H3 phosphorylation, impacting DNA damage responses and transcriptional repression.

Area of Science:

  • Epigenetics
  • Molecular Biology
  • Cancer Research

Background:

  • N-nitroso compounds (NOC) are known carcinogens with poorly understood genotoxic mechanisms.
  • The role of chromatin modifications, particularly histone alterations, in NOC-induced genotoxicity remains largely elusive.

Purpose of the Study:

  • To investigate dynamic histone modification changes following exposure to NOC, specifically N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) and N-methyl-N-nitroso-urea (MNU).
  • To elucidate the control mechanisms of histone H3 phosphorylation changes and their implications for transcriptional repression in response to NOC exposure.

Main Methods:

  • Dynamic analysis of histone modifications, including H3 phosphorylation and H4 acetylation, after MNNG and MNU treatment.
  • Investigating the involvement of poly(ADP-ribosyl)ation enzyme PARP-1, histone kinase VRK1, and tumor suppressor p53 in regulating H3 phosphorylation.

Main Results:

  • A biphasic reduction in histone H3 phosphorylation at serine 10 (H3S10ph) and serine 28 (H3S28ph) was observed upon MNNG and MNU exposure.
  • Histone H4 acetylation rapidly decreased, while H3 hypophosphorylation was found to be dependent on PARP-1, VRK1, and p53.
  • DNA damage-induced down-regulation of H3S10/S28 phosphorylation contributes to transcriptional repression of genes, including cell-cycle regulators.

Conclusions:

  • NOC-induced alkylating damage elicits a biphasic reduction in H3 phosphorylation through distinct regulatory pathways.
  • These epigenetic modifications are integral to DNA damage responses, facilitating repair-associated transcriptional repression.
Keywords:
Chemical carcinogenDNA damage responseEpigeneticsHistone modificationsN-nitroso compounds

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