Clusters of transcription-coupled repair in the human genome

A specialized nucleotide excision repair pathway known as transcription-coupled repair (TCR) counteracts the toxic effects of DNA damage in transcriptionally active genes. The clustering of active genes into gene-rich chromosomal domains predicts that the sites of TCR are unevenly distributed through the genome. To elucidate the genomic organization and chromosomal localization of TCR, we isolated DNA fragments encompassing TCR-mediated repair sites from UV-C irradiated xeroderma pigmentosum group C cells, which can only repair the transcribed strand of active genes. This DNA was used as a molecular probe to visualize TCR in normal metaphase spreads by reverse fluorescence in situ hybridization. Whereas DNA repair sites in normal human cells are evenly distributed through the genome, TCR is highly localized at specific chromosomal domains. Particularly, clusters of TCR sites were identified at early-replicating gene-rich bands and telomeric regions of several chromosomes. High gene-density chromosomes such as chromosome 19 and the GC-rich domains of several chromosomes (T bands) are preferential locations of TCR. Our results demonstrate that the intragenomic localization of TCR resembles the uneven distribution of the human transcriptome, CpG islands, and hyperacetylated histones, enforcing the basic link between DNA repair, transcription, and nuclear organization in a complex genome.