New nucleophilic mechanisms of ros-dependent epigenetic modifications: comparison of aging and cancer

Abstract

It has been shown that ROS (reactive oxygen species, superoxide and hydrogen peroxide) regulate major epigenetic processes, DNA methylation and histone acetylation, although the mechanism of ROS action (ROS signaling) is still unknown. Both DNA methylation and histone acetylation are nucleophilic processes and therefore ROS signaling through typical free radical processes, for example hydrogen atom abstraction is impossible. However, being "super-nucleophile" superoxide can participate in these reactions. Now we propose new nucleophilic mechanisms of DNA methylation and histone modification. During DNA methylation superoxide can deprotonate the cytosine molecule at C-5 position and by this accelerate the reaction of DNA with the positive-charged intermediate S-adenosyl-L-methionine (SAM). Superoxide can also deprotonate histone N-terminal tail lysines and accelerate the formation of their complexes with acetyl-coenzyme A (AcCoA), the supplier of acetyl groups. In cancer cells ROS enhance DNA methylation causing the silencing of tumor suppressor and antioxidant genes and enhancing the proliferation of cancer cells under condition of oxidative stress. ROS signaling in senescent cells probably causes DNA hypomethylation although there are insufficient data for such proposal.

Keywords: DNA Methylation; Histone Modification; Nucleophilic Mechanisms; ROS.

Figure 1.

Nucleophilic mechanism of superoxide-dependent deetherification

Figure 2.

Mechanism of DNA methylation catalyzed by (cytosine-5)-DNMT in which cytosine C5 is attacked by the enzyme nucleophile with the subsequent formation of a transient covalent complex.

Figure 3.

Superoxide-dependent mechanism of DNA methylation.

Figure 4.

Mechanism of superoxide-dependent histone acetylation

Figure 5.

ROS-dependent DNA methylation in cancer and senescent cells