Interference by toxic metal ions with DNA repair processes and cell cycle control: molecular mechanisms.

Abstract

Nickel, cadmium, cobalt, and arsenic compounds are well-known carcinogens to humans and experimental animals. Even though their DNA-damaging potentials are rather weak, they interfere with the nucleotide and base excision repair at low, noncytotoxic concentrations. For example, both water-soluble Ni(II) and particulate black NiO greatly reduced the repair of DNA adducts induced by benzo[a]pyrene, an important environmental pollutant. Furthermore, Ni(II), As(III), and Co(II) interfered with cell cycle progression and cell cycle control in response to ultraviolet C radiation. As potential molecular targets, interactions with so-called zinc finger proteins involved in DNA repair and/or DNA damage signaling were investigated. We observed an inactivation of the bacterial formamidopyrimidine-DNA glycosylase (Fpg), the mammalian xeroderma pigmentosum group A protein (XPA), and the poly(adenosine diphosphate-ribose)polymerase (PARP). Although all proteins were inhibited by Cd(II) and Cu(II), XPA and PARP but not Fpg were inhibited by Co(II) and Ni(II). As(III) deserves special attention, as it inactivated only PARP, but did so at very low concentrations starting from 10 nM. Because DNA is permanently damaged by endogenous and environmental factors, functioning processing of DNA lesions is an important prerequisite for maintaining genomic integrity; its inactivation by metal compounds may therefore constitute an important mechanism of metal-related carcinogenicity.

Environmental exposure to cadmium and risk of cancer: a prospective population-based study

“…30 Third, several studies done in vitro have shown plausible pathways such as increased oxidative stress, 29 modified activity of transcription factors, 31 and inhibition of DNA repair. 32,33 However, the role of these pathways in the response to toxic-metal exposure has not been defined in human beings.…”

Biochemical and Kinetic Characterization of the DNA Helicase and Exonuclease Activities of Werner Syndrome Protein

“…Evidence suggests that environmental metals are co-mutagenic by inhibiting DNA repair (45,46). Since WRN is suggested to have a role in DNA repair and replication, we sought to evaluate the effects of metal ions on WRN by examining WRN helicase activity in the presence of various metals at low micromolar concentrations in reactions that also contained a physiological concentration of Mg 2ϩ (1 mM).…”

Evaluation of gene expression changes in human primary uroepithelial cells following 24‐Hr exposures to inorganic arsenic and its methylated metabolites

“…Arsenic-induced oxidative stress can be attenuated, however, by modulation of cellular thiols [Flora, 2011]. Arsenite has been shown to inhibit poly(ADP-ribose) polymerase-1 (PARP-1), a major enzyme involved in DNA base excision repair by excising 8-hydroxyyl-2 0 -deoxyguanosine (8-OHdG) DNA lesions Wiencke, 1993, 1997;Hartwig et al, 2002;Qin et al, 2008;Zhou et al, 2011]. At exposures 3lM for 24 hr to As III alone in a human keratinocyte cell line (HaCat), no significant increase of ROS or DNA strand breaks was observed and PARP-1 activity was not detected [Qin et al, 2008].…”