Role of base excision repair in maintaining the genetic and epigenetic integrity of CpG sites

Abstract

Cytosine methylation at CpG dinucleotides is a central component of epigenetic regulation in vertebrates, and the base excision repair (BER) pathway is important for maintaining both the genetic stability and the methylation status of CpG sites. This perspective focuses on two enzymes that are of particular importance for the genetic and epigenetic integrity of CpG sites, Methyl Binding Domain 4 (MBD4) and Thymine DNA Glycosylase (TDG). We discuss their capacity for countering C to T mutations at CpG sites, by initiating base excision repair of G·T mismatches generated by deamination of 5-methylcytosine (5mC). We also consider their role in active DNA demethylation, including pathways that are initiated by oxidation and/or deamination of 5mC.

An Intrinsic Epigenetic Barrier for Functional Axon Regeneration

“…Ten-eleven translocation methylcytosine dioxygenases (Tets) have been found to iteratively oxidize 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC) and 5-carboxycytosine (5caC), allowing cell-cycle independent removal of DNA methylation (He et al, 2011; Ito et al, 2011; Tahiliani et al, 2009). Subsequent studies have shown that Tet-initiated DNA oxidation is followed by the thymine DNA glycosylase (TDG)-mediated base excision pathway to complete the demethylation process (Bellacosa and Drohat, 2015; Guo et al, 2011f; He et al, 2011; Ito et al, 2011). Tet family members have been shown to be important for many biological processes including activity-regulated neuronal gene expression, synaptic transmission and scaling, as well as memory formation and extinction (Feng et al, 2015; Kaas et al, 2013; Rudenko et al, 2013; Yu et al, 2015).…”

Structural basis of damage recognition by thymine DNA glycosylase: Key roles for N-terminal residues

“…Thymine DNA glycosylase (TDG) is an enzyme that initiates base excision repair by removing modified forms of 5-methylcytosine (mC) that are generated by deamination or oxidation (1). TDG excises thymine from G·T mispairs, thereby protecting against C→T transition mutations that arise via deamination of mC to T (2,3).…”

Role of Base Excision “Repair” Enzymes in Erasing Epigenetic Marks from DNA

“…Three glycosylases act on G/T mispairs, including TDG (thymine DNA glycosylase), 22,23 MBD4 (methyl binding domain IV), 24–26 and MIG (mismatch DNA glycosylase, Mig-Mth). 27,28 Notably, these G/T mismatch glycosylases excise only thymine from G/T mispairs, as needed to protect against lesions arising by deamination of 5mC to thymine.…”

“…5,26 We provide an overview of active DNA demethylation in this section, to set the stage for a detailed discussion of this important epigenetic process in plants and animals.…”