Pharmacological inhibition of cryptochrome and REV-ERB promotes DNA repair and cell cycle arrest in cisplatin-treated human cells

Abstract Nucleotide excision repair (NER) and cell cycle checkpoints impact the ability of the anti-cancer drug cisplatin to inhibit cell proliferation and induce cell death. Genetic studies have shown that both NER and cell cycle progression are impacted by the circadian clock, which has emerged as...

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Autores principales:	Nadeen Anabtawi, William Cvammen, Michael G. Kemp
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/f2b3929afad44538b799891a484445ab
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spelling	oai:doaj.org-article:f2b3929afad44538b799891a484445ab2021-12-02T19:13:48ZPharmacological inhibition of cryptochrome and REV-ERB promotes DNA repair and cell cycle arrest in cisplatin-treated human cells10.1038/s41598-021-97603-x2045-2322https://doaj.org/article/f2b3929afad44538b799891a484445ab2021-09-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-97603-xhttps://doaj.org/toc/2045-2322Abstract Nucleotide excision repair (NER) and cell cycle checkpoints impact the ability of the anti-cancer drug cisplatin to inhibit cell proliferation and induce cell death. Genetic studies have shown that both NER and cell cycle progression are impacted by the circadian clock, which has emerged as a novel pharmacological target for the treatment of various disease states. In this study, cultured human cell lines were treated with combinations of cisplatin and the circadian clock modulating compounds KS15 and SR8278, which enhance circadian clock transcriptional output by inhibiting the activities of the cryptochrome and REV-ERB proteins, respectively. Treatment of cells with KS15 and SR8278 protected cells against the anti-proliferative effects of cisplatin and increased the expression of NER factor XPA and cell cycle regulators Wee1 and p21 at the mRNA and protein level. Correlated with these molecular changes, KS15 and SR8278 treatment resulted in fewer unrepaired cisplatin–DNA adducts in genomic DNA and a higher fraction of cells in the G1 phase of the cell cycle. Thus, the use of pharmacological agents targeting the circadian clock could be a novel approach to modulate the responses of normal and cancer cells to cisplatin chemotherapy regimens.Nadeen AnabtawiWilliam CvammenMichael G. KempNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-9 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Nadeen Anabtawi William Cvammen Michael G. Kemp Pharmacological inhibition of cryptochrome and REV-ERB promotes DNA repair and cell cycle arrest in cisplatin-treated human cells
description	Abstract Nucleotide excision repair (NER) and cell cycle checkpoints impact the ability of the anti-cancer drug cisplatin to inhibit cell proliferation and induce cell death. Genetic studies have shown that both NER and cell cycle progression are impacted by the circadian clock, which has emerged as a novel pharmacological target for the treatment of various disease states. In this study, cultured human cell lines were treated with combinations of cisplatin and the circadian clock modulating compounds KS15 and SR8278, which enhance circadian clock transcriptional output by inhibiting the activities of the cryptochrome and REV-ERB proteins, respectively. Treatment of cells with KS15 and SR8278 protected cells against the anti-proliferative effects of cisplatin and increased the expression of NER factor XPA and cell cycle regulators Wee1 and p21 at the mRNA and protein level. Correlated with these molecular changes, KS15 and SR8278 treatment resulted in fewer unrepaired cisplatin–DNA adducts in genomic DNA and a higher fraction of cells in the G1 phase of the cell cycle. Thus, the use of pharmacological agents targeting the circadian clock could be a novel approach to modulate the responses of normal and cancer cells to cisplatin chemotherapy regimens.
format	article
author	Nadeen Anabtawi William Cvammen Michael G. Kemp
author_facet	Nadeen Anabtawi William Cvammen Michael G. Kemp
author_sort	Nadeen Anabtawi
title	Pharmacological inhibition of cryptochrome and REV-ERB promotes DNA repair and cell cycle arrest in cisplatin-treated human cells
title_short	Pharmacological inhibition of cryptochrome and REV-ERB promotes DNA repair and cell cycle arrest in cisplatin-treated human cells
title_full	Pharmacological inhibition of cryptochrome and REV-ERB promotes DNA repair and cell cycle arrest in cisplatin-treated human cells
title_fullStr	Pharmacological inhibition of cryptochrome and REV-ERB promotes DNA repair and cell cycle arrest in cisplatin-treated human cells
title_full_unstemmed	Pharmacological inhibition of cryptochrome and REV-ERB promotes DNA repair and cell cycle arrest in cisplatin-treated human cells
title_sort	pharmacological inhibition of cryptochrome and rev-erb promotes dna repair and cell cycle arrest in cisplatin-treated human cells
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/f2b3929afad44538b799891a484445ab
work_keys_str_mv	AT nadeenanabtawi pharmacologicalinhibitionofcryptochromeandreverbpromotesdnarepairandcellcyclearrestincisplatintreatedhumancells AT williamcvammen pharmacologicalinhibitionofcryptochromeandreverbpromotesdnarepairandcellcyclearrestincisplatintreatedhumancells AT michaelgkemp pharmacologicalinhibitionofcryptochromeandreverbpromotesdnarepairandcellcyclearrestincisplatintreatedhumancells
_version_	1718377031433977856

Pharmacological inhibition of cryptochrome and REV-ERB promotes DNA repair and cell cycle arrest in cisplatin-treated human cells

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