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.