Neil3, the final frontier for the DNA glycosylases that recognize oxidative damage

DNA glycosylases are the enzymes that initiate the Base Excision Repair (BER) process that protects all organisms from the mutagenic and/or cytotoxic effects of DNA base lesions. Endonuclease VIII like proteins (Neil1, Neil2 and Neil3) are found in vertebrate genomes and are homologous to the well-characterized bacterial DNA glycosylases, Formamidopyrimidine DNA glycosylase (Fpg) and Endonuclease VIII (Nei). Since the initial discovery of the Neil proteins, much progress has been made on characterizing Neil1 and Neil2. It was not until recently, however, that Neil3 was shown to be a functional DNA glycosylase having a different substrate specificity and unusual structural features compared with other Fpg/Nei homologs. Although the biological functions of Neil3 still remain an enigma, this review highlights recent biochemical and structural data that may ultimately shed light on its biological role.