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Elife. 2018 Feb 5;7. pii: e30842. doi: 10.7554/eLife.30842.

TRAIN (Transcription of Repeats Activates INterferon) in response to chromatin destabilization induced by small molecules in mammalian cells.

Author information

1
Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, United States.
2
Department of Molecular Biology, Ariel University, Ariel, Israel.
3
Buffalo BioLabs, Buffalo, United States.
4
Department of Bioinformatics, Roswell Park Cancer Institute, Buffalo, United States.
5
Department of Chemical Carcinogenesis, Institute of Carcinogenesis, Blokhin Cancer Research Center RAMS, Moscow, Russia.

Abstract

Cellular responses to the loss of genomic stability are well-established, while how mammalian cells respond to chromatin destabilization is largely unknown. We previously found that DNA demethylation on p53-deficient background leads to transcription of repetitive heterochromatin elements, followed by an interferon response, a phenomenon we named TRAIN (Transcription of Repeats Activates INterferon). Here, we report that curaxin, an anticancer small molecule, destabilizing nucleosomes via disruption of histone/DNA interactions, also induces TRAIN. Furthermore, curaxin inhibits oncogene-induced transformation and tumor growth in mice in an interferon-dependent manner, suggesting that anticancer activity of curaxin, previously attributed to p53-activation and NF-kappaB-inhibition, may also involve induction of interferon response to epigenetic derepression of the cellular 'repeatome'. Moreover, we observed that another type of drugs decondensing chromatin, HDAC inhibitor, also induces TRAIN. Thus, we proposed that TRAIN may be one of the mechanisms ensuring epigenetic integrity of mammalian cells via elimination of cells with desilenced chromatin.

KEYWORDS:

CBL0137; TRAIN; cell biology; chromatin; curaxin; human; interferons; mouse; nucleosome

PMID:
29400649
PMCID:
PMC5815852
DOI:
10.7554/eLife.30842
[Indexed for MEDLINE]
Free PMC Article

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