Nucleotide excision repair and its interplay with transcription.
Nucleotide excision repair (NER) is a multistep process capable to remove a variety of DNA distorting lesions from prokaryotic and eukaryotic genomes. In eukaryotic cells, the process requires more than 30 proteins to perform the different steps, i.e. recognition of DNA damage, single strand incisions and excision of the lesion-containing DNA fragment and DNA repair synthesis/ligation. NER can operate via two subpathways: global genome repair (GGR) and a specialized pathway coupled to active transcription (transcription-coupled repair, TCR) and directed to DNA lesions in the transcribed strand of active genes. Both in vivo as well as in cultured cells the fast removal of transcription blocking lesions by TCR is crucial to escape from lethal effects of inhibited transcription inhibition The most delicate step in NER is the recognition of the DNA lesions in their different chromatin context and the mechanism of damage recognition in GGR and TCR is principally different and requires specific proteins. In GGR, the XPC-HR23B is essential for the formation of the incision complex. In TCR the Cockayne syndrome (CS) gene products are key players in the recognition of a stalled RNA polymerase the presumed signaling structure for repair of transcribed strands. In this study, we show that the extent of recovery of UV-inhibited transcription and TCR strictly depends on the amount of CSB protein as well as the amount of DNA damage present in the cell. This indicates that the ratio between DNA damage frequency and CSB protein concentration in the cell is rather critical for acute cellular response, i.e. recovery of inhibited transcription upon DNA damage infliction, and hence cellular survival.
MGC-Department of Toxicogenetics, Leiden University Medical Center, Wassenaarseweg 72, 2333 AL Leiden, The Netherlands.
Anneke
A
van Hoffen
A S
AS
Balajee
Albert A
AA
van Zeeland
Leon H F
LH
Mullenders
D000818:Animals; D003057:Cockayne Syndrome / Q000235:genetics; D004249:DNA Damage / Q000235:genetics; D004260:DNA Repair / Q000235:genetics*; D006801:Humans; D015388:Organelles / Q000235:genetics; D014158:Transcription, Genetic / Q000235:genetics*