Molecular basis of transcriptional mutagenesis at 8-oxoguanine.
Structure-function analysis has revealed the mechanism of yeast RNA polymerase II transcription at 8-oxoguanine (8-oxoG), the major DNA lesion resulting from oxidative stress. When polymerase II encounters 8-oxoG in the DNA template strand, it can misincorporate adenine, which forms a Hoogsteen bp with 8-oxoG at the active center. This requires rotation of the 8-oxoG base from the standard anti- to an uncommon syn-conformation, which likely occurs during 8-oxoG loading into the active site. The misincorporated adenine escapes intrinsic proofreading, resulting in transcriptional mutagenesis that is observed directly by mass spectrometric RNA analysis.
Damsma
Gerke E
GE
Gene Center and Center for Integrated Protein Science Munich (CIPSM), Department of Chemistry and Biochemistry, Ludwig-Maximilians-Universität München, Feodor-Lynen-Strasse 25, 81377 Munich, Germany.
Cramer
Patrick
P
D000225:Adenine / Q000378:metabolism; D018360:Crystallography, X-Ray; D004271:DNA, Fungal / Q000235:genetics*; D006147:Guanine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D016296:Mutagenesis; D011487:Protein Conformation; D012319:RNA Polymerase II / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D012331:RNA, Fungal / Q000235:genetics*; D012441:Saccharomyces cerevisiae / Q000201:enzymology / Q000235:genetics*; D014158:Transcription, Genetic
D004271:DNA, Fungal; D012331:RNA, Fungal; C024829:8-hydroxyguanine; D006147:Guanine; D012319:RNA Polymerase II; D000225:Adenine