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

Katerina Leonova,Ilya Gitlin,Alfiya Safina,Marianna G Yakubovskaya,Igor Koman,Elimelech Nesher,Kirill Kirsanov,Rachel Pratt,Costakis Frangou,Katerina Gurova,Andrei V Gudkov,Brittany Lipchick,Catherine Burkhart,Jianmin Wang,Poorva Sandlesh

doi:10.7554/elife.30842

Katerina Leonova, Ilya Gitlin + Show 13 more

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https://doi.org/10.7554/elife.30842

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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.

Highlights

Control of the integrity of genetic information in cells includes the activation of the DNA damage response, DNA-repair pathways and elimination of cells with damaged DNA
One of the examples that demonstrate the high stability of the cellular epigenome is the well-known, extremely low efficiency of reprogramming of differentiated cells. Another example is the absence of one common ‘cancer cell’ phenotype: transcriptome analysis has clearly demonstrated that tumors, including cell lines propagated for years in culture, bear identifiable traits of the Leonova et al eLife 2018;7:e30842
We have found that nucleosome disassembly caused by curaxin opens multiple Facilitates Chromatin Transcription (FACT)-binding sites, which are normally hidden inside the nucleosome

Summary

Introduction

Control of the integrity of genetic information in cells includes the activation of the DNA damage response, DNA-repair pathways and elimination of cells with damaged DNA (reviewed in [Miller, 2010; Wang and Lindahl, 2016]). One of the examples that demonstrate the high stability of the cellular epigenome is the well-known, extremely low efficiency of reprogramming of differentiated cells (reviewed [Ebrahimi, 2015; Hussein and Nagy, 2012]). Another example is the absence of one common ‘cancer cell’ phenotype: transcriptome analysis has clearly demonstrated that tumors, including cell lines propagated for years in culture, bear identifiable traits of the Leonova et al eLife 2018;7:e30842.

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