Mechanisms of genotoxicity and proteotoxicity induced by the metalloids arsenic and antimony

Abstract

Arsenic and antimony are metalloids with profound effects on biological systems and human health. Both elements are toxic to cells and organisms, and exposure is associated with several pathological conditions including cancer and neurodegenerative disorders. At the same time, arsenic- and antimony-containing compounds are used in the treatment of multiple diseases. Although these metalloids can both cause and cure disease, their modes of molecular action are incompletely understood. The past decades have seen major advances in our understanding of arsenic and antimony toxicity, emphasizing genotoxicity and proteotoxicity as key contributors to pathogenesis. In this review, we highlight mechanisms by which arsenic and antimony cause toxicity, focusing on their genotoxic and proteotoxic effects. The mechanisms used by cells to maintain proteostasis during metalloid exposure are also described. Furthermore, we address how metalloid-induced proteotoxicity may promote neurodegenerative disease and how genotoxicity and proteotoxicity may be interrelated and together contribute to proteinopathies. A deeper understanding of cellular toxicity and response mechanisms and their links to pathogenesis may promote the development of strategies for both disease prevention and treatment.

Keywords: Antimony toxicity; Arsenic toxicity; Genotoxicity; Metalloid; Protein aggregation; Protein folding; Proteostasis; Proteotoxicity.

Fig. 1

How arsenic and antimony cause genotoxicity. Both in yeast and mammalian cells, As(III) and Sb(III) induce oxidative stress to varying degrees. This results in elevated levels of oxidative DNA damage, including oxidized bases and single-strand breaks (SSBs), which can also arise indirectly from incomplete repair of oxidized bases by base excision repair. SSBs can be converted to double strand breaks (DSBs) during replication or when SSBs are closely spaced. In addition, As(III) and Sb(III) increase the formation of protein–DNA adducts such as topoisomerase 1 (TOP1) DNA–protein crosslinks, either in a DNA oxidative damage-dependent manner or by interfering with TOP1 enzymatic activity. The presence of DNA–protein crosslinks leads to generation of replication-associated DSBs and single-stranded DNA (ssDNA) gaps. In budding yeast, oxidative stress and replication-independent DNA damage were also observed after metalloid treatment. In addition, As(III) and Sb(III) not only induce DSBs and ssDNA gaps, but also inhibit repair of these lesions by interfering with DNA damage repair pathways such as homologous recombination (HR), non-homologous end joining (NHEJ) and DNA damage tolerance (DDT). As(III) and Sb(III)-mediated disruption of the actin and microtubule cytoskeleton may also interfere with various aspects of DNA damage repair and cause chromosome aberrations. Finally, both metalloids perturb homeostasis of telomeres by oxidation of guanine-rich telomeric repeats, possibly by directly binding to telomeric DNA or by interfering with the function of telomere-associated proteins. This leads to telomere uncapping resulting in telomere erosion and fusion of chromosome ends. The figure was created with BioRender.com

Fig. 2

How arsenite causes proteotoxicity. A As(III) may bind to free thiols or other functional groups in nascent and non-native proteins, thereby preventing their folding into the native conformation, promoting protein misfolding and aggregation. As(III) may also impair chaperone-mediated folding and disaggregation by binding to the substrate protein, to molecular chaperones, and by modifying the structure of the aggregate. B The protein aggregates formed during As(III) exposure may contribute to toxicity by provoking aberrant protein–protein interactions, by sequestering chaperones, and by increasing the misfolding of other proteins that have not encountered the metalloid. Additionally, As(III) can affect aggregate structure such that processing by chaperones and possibly other PQC factors is impaired. The figure was created with BioRender.com

Fig. 3

How metalloid-induced genotoxicity and proteotoxicity may be interrelated. Arsenic and antimony may induce genotoxicity through oxidative stress, inhibition of DNA repair, perturbation of telomere maintenance, cytoskeletal abnormalities, and epigenetic dysregulation. Arsenite (and perhaps also antimonite) may cause proteotoxicity through oxidative stress, protein misfolding and aggregation and defective aggregate processing. Metalloid-induced genetic alterations may generate proteotoxic stress whereas protein aggregation may lead to enhanced oxidative stress and sequestration of genome maintenance and protein quality-control (PQC) components. Thus, metalloid-induced genotoxicity and proteotoxicity may be interrelated, where loss of genome integrity amplifies the impact of metalloids on proteome integrity and vice versa. In this way, genome instability and proteome instability are interrelated and jointly contribute to neurodegeneration and carcinogenesis. The figure was created with BioRender.com