Biphasic reduction of histone H3 phosphorylation in response to N-nitroso compounds induced DNA damage.
Biochim Biophys Acta
; 1860(9): 1836-44, 2016 09.
Article
em En
| MEDLINE
| ID: mdl-27233451
ABSTRACT
BACKGROUND:
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.METHODS:
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.RESULTS:
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.CONCLUSIONS:
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. GENERALSIGNIFICANCE:
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.Palavras-chave
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Base de dados:
MEDLINE
Assunto principal:
Fosforilação
/
Dano ao DNA
/
Histonas
/
Compostos Nitrosos
Limite:
Humans
Idioma:
En
Revista:
Biochim Biophys Acta
Ano de publicação:
2016
Tipo de documento:
Article
País de afiliação:
China