Title: Chronic arsenic exposure suppresses ATM pathway activation in human keratinocytes.
Authors: Nail, Alexandra N; McCaffrey, Lakynkalina M; Banerjee, Mayukh; Ferragut Cardoso, Ana P; States, J Christopher
Published In Toxicol Appl Pharmacol, (2022 Jul 01)
Abstract: An estimated 220 million people worldwide are chronically exposed to inorganic arsenic (iAs) primarily as a result of drinking iAs-contaminated water. Chronic iAs exposure is associated with a plethora of human diseases including skin lesions and multi-organ cancers. iAs is a known clastogen, inducing DNA double strand breaks (DSBs) in both exposed human populations and in vitro. However, iAs does not directly interact with DNA, suggesting that other mechanisms, such as inhibition of DNA repair and DNA Damage Response (DDR) signaling, may be responsible for iAs-induced clastogenesis. Recent RNA-sequencing data from human keratinocytes (HaCaT cells) indicate that mRNAs for phosphatases important for resolution of DDR signaling are induced as a result of chronic iAs exposure prior to epithelial to mesenchymal transition. Here, we report that phosphorylation of ataxia telengectasia mutated (ATM) protein at a critical site (pSer1981) important for DDR signaling, and downstream CHEK2 activation, are significantly reduced in two human keratinocyte lines as a result of chronic iAs exposure. Moreover, RAD50 expression is reduced in both of these lines, suggesting that suppression of the MRE11-RAD50-NBS1 (MRN) complex may be responsible for reduced ATM activation. Lastly, we demonstrate that DNA double strand break accumulation and DNA damage is significantly higher in human keratinocytes with low dose iAs exposure. Thus, inhibition of the MRN complex in iAs-exposed cells may be responsible for reduced ATM activation and reduced DSB repair by homologous recombination (HR). As a result, cells may favor error-prone DSB repair pathways to fix damaged DNA, predisposing them to chromosomal instability (CIN) and eventual carcinogenesis often seen resulting from chronic iAs exposure.
PubMed ID: 35513056
MeSH Terms: Arsenic*/metabolism; Arsenic*/toxicity; Ataxia; Ataxia Telangiectasia Mutated Proteins*/genetics; Ataxia Telangiectasia Mutated Proteins*/metabolism; Cell Cycle Proteins/genetics; Cell Cycle Proteins/metabolism; DNA Repair; DNA-Binding Proteins/genetics; Epithelial-Mesenchymal Transition; Humans; Keratinocytes*/metabolism; MRE11 Homologue Protein/genetics; MRE11 Homologue Protein/metabolism