Mechanistic Insight Into Cadmium- and Zinc-Induced Inactivation of the Candida albicans Pif1 Helicase.

Bo Zhang,Qintao Zhang,Jiao Jin,Yan Xie,Xiaolei Duan,Xinting Zhu,Kejia Wang,Yang Liu,Dayu Li

doi:10.3389/fmolb.2021.778647

Bo Zhang, Qintao Zhang + Show 7 more

Open Access

https://doi.org/10.3389/fmolb.2021.778647

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Abstract

Zinc and cadmium are environmental contaminants that can cause disease by affecting the activity of DNA-repair proteins. In this study, we investigated the effect of Zn2+ and Cd2+ on the Candida albicans Pif1, a DNA-repair helicase that plays a critical role in ensuring genomic stability. We show that Zn2+ and Cd2+ strongly inhibit both the ATPase and the unwinding activities of CaPif1, but have no effect on its DNA binding activity. High concentrations of Cd2+ may bind to the cysteine residues of CaPif1, and its inhibition appears to be difficult to be restored by ethylene diamine tetraacetic acid, while inhibition due to Zn2+ can. When the two ions are at low concentrations, increasing the concentration of ATP in the reaction can appropriately weaken the inhibitory effect of Zn2+, while cysteine can reduce the inhibitory effect of Cd2+. In addition, we found that for both Cd2+ and Zn2+ the inhibition effects were nearly 100 times greater in reduced environments than in non-reducing environments. When heavy metals stimulate the body’s response, the environment of the body becomes less reducing, and thus the tolerance of CaPif1 to heavy metals will be stronger. We propose that CaPif1 may resist the toxicity of heavy metals through this mechanism. Altogether, our results provide new insights into the mechanisms by which heavy metals are toxic to DNA-repair proteins.

Highlights

With the development of society, an increasing amount of heavy metals are released into the environment through industry and agriculture
We investigated and characterized the biochemical activity and substrate specificity of Candida albicans Pif1 (CaPif1) and the impact of six heavy metal ions, manganese (Mn2+), calcium (Ca2+), zinc (Zn2+), nickel (Ni2+), copper (Cu2+), and cadmium (Cd2+), on its activity
It was found that CaPif1 with blunt end dsDNA had very weak binding activity, while the other two substrates containing single-stranded tail structures showed high affinity

Summary

Introduction

With the development of society, an increasing amount of heavy metals are released into the environment through industry and agriculture. Heavy metals tend to bioaccumulate, display biomagnification, and are toxic, which can lead to a variety of human diseases. They damage the kidneys, cause harm to the lungs upon inhalation, and interfere with bone metabolism (Maret and Moulis, 2013). Zinc’s chemical and physical properties are similar to those of cadmium (Brzoska, 2001), but the biological effects of these two heavy metals are quite different. It has been proven that cadmium causes cancer

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