Cytosine hydroxymethylation by TET enzymes: From the control of gene expression to the regulation of DNA repair mechanisms, and back

Audrey Lejart,Univ Rennes, Cnrs, Igdr-Umr 6290, F35000 Rennes, France ,Gilles Salbert,Sébastien Huet

doi:10.3934/biophy.2018.3.182

Abstract

Chromatin is a complex multi-scale structure composed of DNA wrapped around nucleosomes. The compaction state is finely regulated mainly by epigenetic marks present not only on nucleosomes but also on the DNA itself. The most studied DNA post-transcriptional modification is 5-methylcytosine (5-mC). Methylation of the cytosine at CpG islands localized at the promoter is associated with repression of transcription. On the contrary, enrichment of 5-hydroxymethylcytosine (5-hmC), one of the oxidation products of 5-mC by TET (ten-eleven translocation) enzymes, on promoters and enhancers promotes transcription activation. Recently, a new role of 5-hmC has been proposed in the context of DNA repair. 5-hmC was found to be enriched at DNA lesions and knockdown of TET led to impaired repair efficiency. Here, we review our current knowledge regarding the role of the regulation of the 5-mC/5-hmC balance by TET enzymes in the context of transcription modulation as well as DNA repair processes. In a final section, we speculate on the potential involvement of TET proteins in DNA repair mechanisms associated with transcription activation.

Highlights

Research work performed over the last fifty years have shown that our genetic material is not a linear sequence of 3 billion base pairs coding for all the proteins required by the cell
Methylation of the cytosine at CpG islands localized at the promoter is associated with repression of transcription
We speculate on the potential involvement of TET proteins in DNA repair mechanisms associated with transcription activation

Summary

Introduction

Research work performed over the last fifty years have shown that our genetic material is not a linear sequence of 3 billion base pairs coding for all the proteins required by the cell. While the direct impact of methylated cytosines (5-mC) on chromatin structure remains unclear, this mark shows key signaling functions in relation to transcription regulation. Depending on their CpG density, promoters enriched in 5-mC at CpG sites tend to have a lower transcription rate, a fact that has been attributed to a lack of transcription factor binding [6]. Activation induced deaminases (AID), which deaminate cytosine into uracil, are able to convert 5mC into thymidine, yet with a lower efficiency [11] The relevance of this 5-mC clearance pathway, which later involves the Base Excision Repair (BER) machinery to replace the thymidine by a cytosine, remains debated [12]. Despite sharing the same catalytic activity, these proteins are expressed differentially during development and are present in different cell types, suggesting that they may fulfill different functions [18]

AIMS Biophysics

An emerging role for TET enzymes in DNA repair mechanisms