Lack of transcription-coupled repair of acetylaminofluorene DNA adducts in human fibroblasts contrasts their efficient inhibition of transcription.
The N-(deoxyguanosine-8-yl)-2-acetylaminofluorene (dG-C8-AAF) lesion is among the most helix distorting DNA lesions. In normal fibroblasts dG-C8-AAF is repaired rapidly in transcriptionally active genes, but without strand specificity, indicating that repair of dG-C8-AAF by global genome repair (GGR) overrules transcription-coupled repair (TCR). Yet, dG-C8-AAF is a very potent inhibitor of transcription. The target size of inhibition (45 kilobases) suggests that transcription inhibition by dG-C8-AAF is caused by blockage of initiation rather than elongation. Cockayne's syndrome (CS) cells appear to be extremely sensitive to the cytotoxic effects of dG-C8-AAF and are unable to recover inhibited RNA synthesis. However, CS cells exhibit no detectable defect in repair of dG-C8-AAF in active genes, indicating that impaired TCR is not the cause of the enhanced sensitivity of CS cells. These and data reported previously suggest that the degree of DNA helix distortion determines the rate of GGR as well as the extent of inhibition of transcription initiation. An interchange of the transcription/repair factor TFIIH from promoter sites to sites of damage might underlie inhibition of transcription initiation. This process is likely to occur more rapidly and efficiently in the case of strongly DNA helix distorting lesions, resulting in a very efficient GGR, a poor contribution of TCR to repair of lesions in active genes, and an efficient inhibition of transcription.
van Oosterwijk
M F
MF
Department of Radiation Genetics and Chemical Mutagenesis, Medical Genetics Center, Leiden University, 2333 AL Leiden, The Netherlands.
Filon
R
R
de Groot
A J
AJ
van Zeeland
A A
AA
Mullenders
L H
LH
D015073:2-Acetylaminofluorene / Q000031:analogs & derivatives* / Q000378:metabolism; D002478:Cells, Cultured; D018736:DNA Adducts / Q000235:genetics*; D004260:DNA Repair / Q000235:genetics*; D004261:DNA Replication; D003849:Deoxyguanosine / Q000031:analogs & derivatives* / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D014158:Transcription, Genetic / Q000235:genetics*
D018736:DNA Adducts; C018776:N-(deoxyguanosin-8-yl)acetylaminofluorene; D015073:2-Acetylaminofluorene; D003849:Deoxyguanosine