Mechanism and Catalytic Site Atlas

The genetic integrity of cells depends on the concerted action of repair enzymes that recognise and excise damaged bases and mutagenic lesions from DNA. The primary defence against these genotoxic insults is the DNA base excision repair (BER) pathway. The first step of BER is initiated by many distinct DNA glycosylases that each recognise a specific class of damaged DNA nucleotide and cleave the N-C1' glycosidic bond, linking the aberrant base to the deoxyribose sugar. These damage-specific glycosyllases generate as a common product apurinic/apyrimidinic (AP or abasic) sites, which are inherently toxic and mutagenic and thus must be rapidly processed and removed. In the subsequent damage-general steps of single nucleotide BER, an AP endonuclease cleaves the DNA backbone at AP sites, providing a product that is further processed by a DNA deoxyribosephosphodiesterase, a DNA polymerase, and a DNA ligase [PMID:10458614].

Endo IV is an ~30kDa Zn(II) -dependent endonuclease that, unlike the Mg(II) -dependent AP endonuclease III and APE-1, resists inactivation by EDTA. The purified enzyme specifically cleaves the DNA backbone at AP sites and also removes 3'-DNA-blocking groups such as 3' phosphate, 3' phosphoglycolates, and 3' alpha,beta-unsaturated aldehydes that arise from oxidative base damage and the activity of combined glycosylase/lyase enzymes [PMID:10458614].