DNA repair domains within a human gene: selective repair of sequences near the transcription initiation site

Abstract

We describe a new form of DNA repair heterogeneity along the genome. The repair rate of UV-induced cyclobutane pyrimidine dimers (CPDs) was measured at single nucleotide resolution along the promoter and transcribed sequences of the human JUN gene in UV-irradiated diploid fibroblasts. The promoter of this gene contains an array of sequence-specific transcription factors located between nucleotides -200 and -50 relative to the major transcription start site. These sequences are repaired slowly; at many sites >50% of the CPDs are left unrepaired after 24 h. However, repair rates are 10-fold faster near the transcription initiation site. This very fast repair is seen on both DNA strands between nucleotides -40 and +100 where at most positions >90% of the dimers are repaired within 4 h. There is a general gradient of repair efficiency of the transcribed DNA strand with faster repair within the 5'-end and diminished repair towards the 3'-end of the gene. The fast repair rates seen near the transcription initiation site may be explained by increased local concentrations of DNA repair factors that are associated with general transcription factors (e.g. TFIIH) functioning in transcription initiation. This domain-specific DNA repair may aid in maintaining transcription initiation of essential genes after DNA damage.