Physiological concentrations of glucocorticoids induce pathological DNA double-strand breaks

概要

Nuclear receptors induce rapid transcriptional responses
as transcription factors upon binding to ligands, including androgen, estrogens, and corticosteroids together
termed “steroid” hormones. Corticosteroids are produced
in the adrenal cortex and include two main classes, glucocorticoids (GCs) and mineralocorticoids. Cortisol is the
most crucial GC in the human body and is essential for
life (Russell & Lightman, 2019). GCs bind to the glucocorticoid receptor (GR), and ligand-bound GR regulates
the transcription of numerous GR-target genes as a transcription factor. GR-mediated signaling suppresses
immune cells, and dexamethasone (Dex), a synthetic GC,
has been widely used clinically for suppressing immune
reactions in patients with allergies, autoimmune diseases,
organ transplantations, and COVID-19 (Cain &
Cidlowski, 2020; Strehl et al., 2019). Cortisol binds to
both GR and mineralocorticoid receptors, whereas Dex
binds only to GR (Heming et al., 2018). Dex has
50
times more potent GR-stimulating activity than the cortisol (Heming et al., 2018). Serum cortisol is at 80–700
nano Molar (nM) (Huang et al., 2007; Scheer et al., 2002),
and the clinically relevant concentration of Dex is 6–
250 nM (Spoorenberg et al., 2014; Weijtens et al., 1998).
DNA Topoisomerase II (TOP2) plays a vital role in
transcriptional responses to various extracellular signals,
including nuclear-receptor ligands, cytokines, neuro´
transmitters, and heat shock (Alvarez-Quil

on et al., 2014;
Bunch, 2017; Bunch et al., 2014, 2015; Calderwood, 2016;
Haffner et al., 2010; Itou et al., 2020; Ju et al., 2006;
Madabhushi et al., 2015; McKinnon, 2016; Miyaji
et al., 2020; Sano et al., 2008; Wong et al., 2009) (reviewed
in [Pommier et al., 2022; Pommier et al., 2016]). TOP2 is
also required for the elongation of the transcription
(Austin et al., 2018; Joshi et al., 2012; King et al., 2013).
There are two TOP2 enzymes (TOP2A and TOP2B), and
TOP2A is expressed mainly in cycling cells while TOP2B
is ubiquitously expressed (reviewed in [Austin et al.,
2018]). TOP2A plays essential roles in DNA replication,
decatenation of entangled, newly replicated sister chromatids, as well as condensation of mitotic chromosomes
(reviewed in [Nitiss, 2009; Pommier et al., 2016]). ...

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