Physiological concentrations of glucocorticoids induce pathological DNA double-strand breaks.

Publisher: Blackwell Science Ltd Country of Publication: England NLM ID: 9607379 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1365-2443 (Electronic) Linking ISSN: 13569597 NLM ISO Abbreviation: Genes Cells Subsets: MEDLINE

Original Publication: Oxford, UK : Blackwell Science Ltd., 1996-

DNA Breaks, Double-Stranded* ; Transcription Factors*/metabolism; DNA-Binding Proteins/metabolism ; Glucocorticoids/pharmacology ; DNA Repair ; Nuclear Proteins/metabolism ; Hydrocortisone/pharmacology ; Phosphoric Diester Hydrolases/genetics ; Phosphoric Diester Hydrolases/metabolism ; DNA Topoisomerases, Type II/genetics ; DNA Topoisomerases, Type II/metabolism ; DNA/genetics

Steroid hormones induce the transcription of target genes by activating nuclear receptors. Early transcriptional response to various stimuli, including hormones, involves the active catalysis of topoisomerase II (TOP2) at transcription regulatory sequences. TOP2 untangles DNAs by transiently generating double-strand breaks (DSBs), where TOP2 covalently binds to DSB ends. When TOP2 fails to rejoin, called "abortive" catalysis, the resulting DSBs are repaired by tyrosyl-DNA phosphodiesterase 2 (TDP2) and non-homologous end-joining (NHEJ). A steroid, cortisol, is the most important glucocorticoid, and dexamethasone (Dex), a synthetic glucocorticoid, is widely used for suppressing inflammation in clinics. We here revealed that clinically relevant concentrations of Dex and physiological concentrations of cortisol efficiently induce DSBs in G 1 phase cells deficient in TDP2 and NHEJ. The DSB induction depends on glucocorticoid receptor (GR) and TOP2. Considering the specific role of TDP2 in removing TOP2 adducts from DSB ends, induced DSBs most likely represent stalled TOP2-DSB complexes. Inhibition of RNA polymerase II suppressed the DSBs formation only modestly in the G 1 phase. We propose that cortisol and Dex frequently generate DSBs through the abortive catalysis of TOP2 at transcriptional regulatory sequences, including promoters or enhancers, where active TOP2 catalysis occurs during early transcriptional response.
(© 2022 Molecular Biology Society of Japan and John Wiley & Sons Australia, Ltd.)

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19H04267 JSPS KAKENHI; 19K20449 JSPS KAKENHI; 20KK0186 JSPS KAKENHI; 18H03992 JSPS KAKENHI; 16H06306 JSPS KAKENHI; 20K16280 JSPS KAKENHI; 20K21525 JSPS KAKENHI; 21K07148 JSPS KAKENHI; 16H12595 JSPS KAKENHI

Keywords: DNA topoisomerase II; DSB repair; TDP2/EAPII/TTRAP; cortisol; dexamethasone; early transcriptional response; glucocorticoid; signal-induced transcription

0 (Transcription Factors)
0 (DNA-Binding Proteins)
0 (Glucocorticoids)
0 (Nuclear Proteins)
WI4X0X7BPJ (Hydrocortisone)
EC 3.1.4.- (Phosphoric Diester Hydrolases)
EC 5.99.1.3 (DNA Topoisomerases, Type II)
9007-49-2 (DNA)

Date Created: 20221123 Date Completed: 20230118 Latest Revision: 20240307

20240307

10.1111/gtc.12993

36415926