Comparative Effects of Mercury(II) and Cadmium on MutS Homolog 6(MSH6)-Mediated DNA Mismatch Binding Activities in Zebrafish (Danio rerio) Embryos

Abstract

MutS homolog 6 (MSH6) of the MSH2-MSH6 complex binds simple mispairs and small insertion-deletion loops (IDL) then initiates DNA mismatch repair in eukaryotes. We have shown the ability of Cd(2+) to downregulate msh2/msh6 expression in zebrafish embryos via oxidative stress. This study explored the effects of Cd(2+) and Hg(2+) on MSH6-mediated mismatch binding activities. MSH6-mediated G-T and IDL-specific binding activities were significantly inhibited at similar levels after exposing zebrafish embryos at 1 h postfertilization) to HgCl2 or CdCl2 at 1.0 to 2.5 μM for 9 h, but MSH6 synthesis was found to be less sensitive to Hg(2+) than to Cd(2+) . Real-time RT-PCR and in situ hybridization also detected a weaker susceptibility of MSH gene transcription to Hg(2+) . The weaker response of MSH gene activities to Hg(2+) correlated with the lower oxidative stress-inducing potential of Hg(2+) . Hence, Hg(2+) targets mismatch sensing capacity at protein function rather than at transcription level.

DNA repair genes play a variety of roles in the development of fish embryos

“…Cadmium-induced oxidative stress also ensued downregulation in the expression of MMR genes, msh2 and msh6, in one hpf zebrafish embryos when subjected to sub-lethal concentrations (3-5 µM) of Cd 2+ (Hsu et al, 2013). The inhibition of Msh6 protein binding activity was recorded after exposure of one hpf zebrafish embryos to Cd 2+ (Ho et al, 2015). Exposure to Cd 2+ during zebrafish embryo development was not associated with significant mortality or teratogenicity at larval stage but led to changes in behavior compared to control (Shankar et al, 2021).…”

“…Hg 2+ has been shown to cause DNA strand breaks through oxidative stress and to impede DNA repair machinery (Rooney, 2007;Barcelos et al, 2011). Hg 2+ had different effects on Msh6 protein synthesis and msh2, msh6 mRNA expression (Ho et al, 2015). Msh6 protein synthesis was inhibited without causing msh6 mRNA expression to be downregulated.…”