Neddylation inhibits CtIP-mediated resection and regulates DNA double strand break repair pathway choice.

Sonia Jimeno,Pablo Huertas,Cristina Cepeda-García,Andrés Cruz-García,Daniel Gómez-Cabello,María Jesús Fernández-Ávila

doi:10.1093/nar/gku1384

Abstract

DNA double strand breaks are the most cytotoxic lesions that can occur on the DNA. They can be repaired by different mechanisms and optimal survival requires a tight control between them. Here we uncover protein deneddylation as a major controller of repair pathway choice. Neddylation inhibition changes the normal repair profile toward an increase on homologous recombination. Indeed, RNF111/UBE2M-mediated neddylation acts as an inhibitor of BRCA1 and CtIP-mediated DNA end resection, a key process in repair pathway choice. By controlling the length of ssDNA produced during DNA resection, protein neddylation not only affects the choice between NHEJ and homologous recombination but also controls the balance between different recombination subpathways. Thus, protein neddylation status has a great impact in the way cells respond to DNA breaks.

Highlights

DNA is constantly challenged by physical and chemical threats that compromise its structure and function [1]
The balance between Non-homologous end-joining (NHEJ) and homologous recombination (HR) is essential for optimal DNA repair
Upon creating a double strand breaks (DSBs) using the nuclease ISceI, the reporter can be repaired by either NHEJ, rendering an active Green Fluorescent Protein (GFP) gene, or by a subtype of HR known as SSA, rendering an active RFP gene

Summary

Introduction

DNA is constantly challenged by physical and chemical threats that compromise its structure and function [1]. Those alterations are known as DNA lesions and have to be eliminated in a process called DNA repair. To facilitate the repair of DNA, several molecular machineries have to be coordinated with the rest of the cellular metabolism This is true when repairing DNA molecules in which both strands have been broken, the so-called DNA double strand breaks (DSBs). Upon DSB appearance a complex process known as the DNA damage response (DDR) is activated in order to sense and repair the breaks, and to coordinate cell cycle progression, transcription, cellular metabolism, etc. The DDR is a fast response that relies mainly in the alterations of the profiles of post-translational modifications of many different proteins, such as phosphorylation, neddylation, ubiquitylation or sumoylation [2,4]

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Results

Conclusion