The Alkylating Agent Methyl Methanesulfonate Triggers Lipid Alterations at the Inner Nuclear Membrane That Are Independent from Its DNA-Damaging Ability.

Sara Ovejero,María Moriel-Carretero,Caroline Soulet

doi:10.3390/ijms22147461

Abstract

In order to tackle the study of DNA repair pathways, the physical and chemical agents creating DNA damage, the genotoxins, are frequently employed. Despite their utility, their effects are rarely restricted to DNA, and therefore simultaneously harm other cell biomolecules. Methyl methanesulfonate (MMS) is an alkylating agent that acts on DNA by preferentially methylating guanine and adenine bases. It is broadly used both in basic genome stability research and as a model for mechanistic studies to understand how alkylating agents work, such as those used in chemotherapy. Nevertheless, MMS exerts additional actions, such as oxidation and acetylation of proteins. In this work, we introduce the important notion that MMS also triggers a lipid stress that stems from and affects the inner nuclear membrane. The inner nuclear membrane plays an essential role in virtually all genome stability maintenance pathways. Thus, we want to raise awareness that the relative contribution of lipid and genotoxic stresses when using MMS may be difficult to dissect and will matter in the conclusions drawn from those studies.

Highlights

The study of genome stability maintenance pathways frequently involves the use of tools to create DNA damage
During our studies to evaluate the potential impact of genotoxins on the formation of lipid droplets in RPE-1 cells, we realized that 2 h treatment with the alkylating agent Methyl methanesulfonate (MMS) induced the formation of nuclear lipid droplets
Lipid droplets are organelles shielded by a phospholipid monolayer that store lipids and arise from the endoplasmic reticulum (ER), in this case from the inner nuclear membrane (INM) subdomain and into the nucleoplasm [8]

Summary

Introduction

The study of genome stability maintenance pathways frequently involves the use of tools to create DNA damage. These can be of a genetic nature, for example by removing a gene whose product protein is important for the repair of DNA lesions, which accumulate. DNA damage can be created by external interventions such as the use of physical and chemical agents (genotoxins). Apart from chemicals, physical approaches trigger collateral effects. As such, creating single- and doublestrand breaks in the DNA with ionizing radiation provokes the additional cleavage of sphingosine moieties at the plasma membrane, releasing ceramides, which can trigger apoptosis faster than the simultaneous breaks occurring in the DNA [3]

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Conclusion