The Fpg/Nei Family of DNA Glycosylases

Abstract

During the initial stages of the base excision DNA repair (BER) pathway, DNA glycosylases are responsible for locating and removing the majority of endogenous oxidative base lesions. The bifunctional formamidopyrimidine DNA glycosylase (Fpg) and endonuclease VIII (Nei) are members of the Fpg/Nei family, one of the two families of glycosylases that recognize oxidized DNA bases, the other being the HhH/GPD (or Nth) superfamily. Structural and biochemical developments over the past decades have led to novel insights into the mechanism of damage recognition by the Fpg/Nei family of enzymes. Despite the overall structural similarity among members of this family, these enzymes exhibit distinct features that make them unique. This review summarizes the current structural knowledge of the Fpg/Nei family members, emphasizes their substrate specificities, and describes how these enzymes search for lesions.

A highly conserved family of domains related to the DNA-glycosylase fold helps predict multiple novel pathways for RNA modifications

“…While more speculative in nature, it is possible to obtain certain clues regarding the nature of the potential target of the predicted NFACT-N catalytic domain: if NFACT-N were to act similar to FMN-DG, then among the endogenous bases in RNA uridine or cytidine contain spatially comparable carbonyl groups to FMN-DG substrates 18 . In addition to formation of pseudouridine and several pseudouridine derivatives, a range of rRNA base modifications have been previously characterized and include various forms of methylated, hydroxylated, and acetylated bases 59 , 60 .…”

“…Here we identify and characterize the distinct globular domains conserved across all members of the gene family in addition to the HhH domain pair. One of these domains is predicted to be an enzymatic domain related to the bifunctional DNA glycosylase/endonuclease domain involved in Base Excision Repair (BER), commonly referred to as the Formamidopyrimidine, MutM, and Nei/EndoVIII DNA glycosylase (FMN-DG; also referred to in the literature as Fpg/Nei, Fapy DNA glycosylase, glycosylase/AP-lyase, or Endonuclease VIII) domain 15 - 18 . We identify shared and distinct features of the active site of these two related domains, implying both similarities and differences in their catalytic mechanisms.…”

CABRA: Cluster and Annotate Blast Results Algorithm

“…The functional and structural information that can be drawn from each protein group is different and therefore they would have to be looked upon separately. Using CABRA, the on-the-fly annotation of the clusters eases the interpretation of the results, identifying the FPG proteins as bacterial and the H2TH domain as the common link between all BLAST results, as described in the bibliography [10]. …”

Base excision repair: A critical player in many games

“…The mammalian DNA glycosylases that recognize base damages all have structural or functional homologs in bacteria and in fact the human enzymes are able to complement repair defects in bacteria (for reviews see [3,4]). The human mono-functional glycosylases recognize a broad spectrum of lesions.…”

“…The crystal structures also revealed conformational changes upon Pol β binding to DNA. The crystal structures of ligase I (for reviews see [4,20,21]) bound to DNA reveal those subdomains that encircle DNA and the position of the nicked DNA ends within the ligase active site. In addition to its repair function, ligase l functions during DNA replication of Okazaki fragments.…”