Acetylation of human 8-oxoguanine-DNA glycosylase by p300 and its role in 8-oxoguanine repair in vivo.
The human 8-oxoguanine-DNA glycosylase 1 (OGG1) is the major DNA glycosylase responsible for repair of 7,8-dihydro-8-oxoguanine (8-oxoG) and ring-opened fapyguanine, critical mutagenic DNA lesions that are induced by reactive oxygen species. Here we show that OGG1 is acetylated by p300 in vivo predominantly at Lys338/Lys341. About 20% of OGG1 is present in acetylated form in HeLa cells. Acetylation significantly increases OGG1's activity in vitro in the presence of AP-endonuclease by reducing its affinity for the abasic (AP) site product. The enhanced rate of repair of 8-oxoG in the genome by wild-type OGG1 but not the K338R/K341R mutant, ectopically expressed in oxidatively stressed OGG1-null mouse embryonic fibroblasts, suggests that acetylation increases OGG1 activity in vivo. At the same time, acetylation of OGG1 was increased by about 2.5-fold after oxidative stress with no change at the polypeptide level. OGG1 interacts with class I histone deacetylases, which may be responsible for its deacetylation. Based on these results, we propose a novel regulatory function of OGG1 acetylation in repair of its substrates in oxidatively stressed cells.
Sealy Center for Molecular Science, University of Texas Medical Branch, 6.136 Medical Research Building, Route 1079, Galveston, TX 77555, USA.
Kishor K
KK
Bhakat
Sanath K
SK
Mokkapati
Istvan
I
Boldogh
Tapas K
TK
Hazra
Sankar
S
Mitra
D000107:Acetylation; D045647:DNA Glycosylases / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism*; D004260:DNA Repair / Q000502:physiology*; D006147:Guanine / Q000031:analogs & derivatives* / Q000378:metabolism; D006367:HeLa Cells; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D008239:Lysine / Q000378:metabolism; D009154:Mutation; D018384:Oxidative Stress; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D050880:p300-CBP Transcription Factors / Q000378:metabolism*
D011994:Recombinant Proteins; C024829:8-hydroxyguanine; D006147:Guanine; D050880:p300-CBP Transcription Factors; D045647:DNA Glycosylases; C479058:oxoguanine glycosylase 1, human; D006655:Histone Deacetylases; D008239:Lysine