MBD4 and TDG: Multifaceted DNA glycosylases with ever expanding biological roles

The base excision repair system is vital to the repair of endogenous and exogenous DNA damage. This pathway is initiated by one of several DNA glycosylases that recognizes and excises specific DNA lesions in a coordinated fashion. Methyl-CpG Domain Protein 4 (MBD4) and Thymine DNA Glycosylase (TDG) are the two major G:T glycosylases that remove thymine generated by the deamination of 5-methylcytosine. Both of these glycosylases also remove a variety of other base lesions, including G:U and preferentially act at CpG sites throughout the genome. Many have questioned the purpose of seemingly redundant glycosylases, but new information has emerged to suggest MBD4 and TDG have diverse biological functions. MBD4 has been closely linked to apoptosis, while TDG has been clearly implicated in transcriptional regulation. This article reviews all of these developments, and discusses the consequences of germline and somatic mutations that lead to non-synonymous amino acid substitutions on MBD4 and TDG protein function. In addition, we report the finding of alternatively spliced variants of MBD4 and TDG and the results of functional studies of a tumor-associated variant of MBD4.