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  • Original Article
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p21WAF1 gene promoter is epigenetically silenced by CTIP2 and SUV39H1

Abstract

Mainly regulated at the transcriptional level, the cellular cyclin-dependent kinase inhibitor, CDKN1A/p21WAF1 (p21), is a major cell cycle regulator of the response to DNA damage, senescence and tumor suppression. Here, we report that COUP-TF-interacting protein 2 (CTIP2), recruited to the p21 gene promoter, silenced p21 gene transcription through interactions with histone deacetylases and methyltransferases. Importantly, treatment with the specific SUV39H1 inhibitor, chaetocin, repressed histone H3 lysine 9 trimethylation at the p21 gene promoter, stimulated p21 gene expression and induced cell cycle arrest. In addition, CTIP2 and SUV39H1 were recruited to the silenced p21 gene promoter to cooperatively inhibit p21 gene transcription. Induction of p21WAF1 gene upon human immunodeficiency virus 1 (HIV-1) infection benefits viral expression in macrophages. Here, we report that CTIP2 further abolishes Vpr-mediated stimulation of p21, thereby indirectly contributing to HIV-1 latency. Altogether, our results suggest that CTIP2 is a constitutive p21 gene suppressor that cooperates with SUV39H1 and histone methylation to silence the p21 gene transcription.

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Acknowledgements

We thank Dr D Kardassis for providing us with p21-LUC plasmids and Dr Yannick Goumon for his technical support. This work was supported by the Institut National de la Santé et de la Recherche Médicale (INSERM), by grants from the Agence Nationale de Recherches sur le SIDA (ANRS) to OR and CVL, from Sidaction to OR and TC and from the French Ministry of Research (‘ACI JC 5364’ to OR and doctoral grant to TC and SS) The work in CVL's laboratory was supported by grants from the ‘Fonds National de la Recherche Scientifique’ (FNRS, Belgium), the Télévie-Program of the FNRS, from the ‘Action de Recherche concertée du Ministère de la Communauté Française’ (ULB, ARC program no. 04/09-309), from the Internationale Brachet Stiftung (IBS), from the Région Wallonne-Commission Européenne FEDER (Intergenes Project, Interreg III program) and from the Theyskens-Mineur Foundation. CVL is ‘Directeur de Recherches’ of the FNRS. This work was supported by NIH to BES.

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Correspondence to C Van Lint or O Rohr.

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Cherrier, T., Suzanne, S., Redel, L. et al. p21WAF1 gene promoter is epigenetically silenced by CTIP2 and SUV39H1. Oncogene 28, 3380–3389 (2009). https://doi.org/10.1038/onc.2009.193

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