Stimulation of DNA glycosylase activity of OGG1 by NEIL1: functional collaboration between two human DNA glycosylases.
The eukaryotic 8-oxoguanine-DNA glycosylase 1 (OGG1) provides the major activity for repairing mutagenic 7,8-dihydro-8-oxoguanine (8-oxoG) induced in the genome due to oxidative stress. Earlier in vitro studies showed that, after excising the base lesion, the human OGG1 remains bound to the resulting abasic (AP) site in DNA and does not turn over efficiently. The human AP-endonuclease (APE1), which cleaves the phosphodiester bond 5' to the AP site, in the next step of repair, displaces the bound OGG1 and thus increases its turnover. Here we show that NEIL1, a DNA glycosylase/AP lyase specific for many oxidized bases but with weak 8-oxoG excision activity, stimulates turnover of OGG1 in a fashion similar to that of APE1 and carries out betadelta-elimination at the AP site. This novel collaboration of two DNA glycosylases, which do not stably interact with each other, in stimulating 8-oxoguanine repair is possible because of higher AP site affinity and stronger AP lyase activity of NEIL1 relative to OGG1. Comparable levels of NEIL1 and OGG1 in some human cells raise the possibility that NEIL1 serves as a backup enzyme to APE1 in stimulating 8-oxoG repair in vivo.
Mokkapati
Sanath K
SK
Sealy Center for Molecular Science, University of Texas Medical Branch, Galveston, Texas 77550, USA.
Wiederhold
Lee
L
Hazra
Tapas K
TK
Mitra
Sankar
S
D001667:Binding, Competitive; D045647:DNA Glycosylases / Q000737:chemistry / Q000378:metabolism* / Q000502:physiology*; D004260:DNA Repair / Q000502:physiology; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000737:chemistry / Q000502:physiology*; D004789:Enzyme Activation / Q000502:physiology; D020536:Enzyme Activators / Q000737:chemistry*; D005663:Furans / Q000737:chemistry; D006151:Guanosine / Q000031:analogs & derivatives* / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D007700:Kinetics; D011485:Protein Binding; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D013379:Substrate Specificity
D020536:Enzyme Activators; D005663:Furans; D011994:Recombinant Proteins; D006151:Guanosine; C046215:8-hydroxyguanosine; C018674:tetrahydrofuran; D045647:DNA Glycosylases; C473634:NEIL1 protein, human; C479058:oxoguanine glycosylase 1, human; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase