DNA excision repair: where do all the dimers go?

Abstract

Exposure of cells to UV light from the sun causes the formation of pyrimidine dimers in DNA that have the potential to lead to mutation and cancer. In humans, pyrimidine dimers are removed from the genome in the form of ~30 nt-long oligomers by concerted dual incisions. Though nearly 50 y of excision repair research has uncovered many details of UV photoproduct damage recognition and removal, the fate of the excised oligonucleotides and, in particular, the ultimate fate of the chemically very stable pyrimidine dimers remain unknown. Physiologically relevant UV doses introduce hundreds of thousands of pyrimidine dimers in diploid human cells, which are excised from the genome within ~24 h. Once removed from the genome, "where do all the dimers go?" In a recent study we addressed this question. Although our study did not determine the fate of the dimer itself, it revealed that the excised ~30-mer is released from the duplex in a tight complex with the transcription/repair factor TFIIH. This finding combined with recent reports that base and oligonucleotide products of the base and double-strand break repair pathways also make stable complexes with the cognate repair enzymes, and that these complexes activate the MAP kinase and checkpoint signaling pathways, respectively, raises the possibility that TFIIH-30-mer excision complexes may play a role in signaling reactions in response to UV damage.

Figure 1. DNA base damage induced by UV. Exposure of adjacent thymidine bases in DNA results in formation of (6–4) photoproducts and cyclobutane thymidine dimers.

Figure 2. Model of human nucleotide excision repair. UV-induced thymine dimers (T<>T) are recognized by the actions of XPA, RPA, and XPC-TFIIH and DNA is unwound around the dimer by the helicase activity of TFIIH. Following dual incisions by the XPF and XPG nucleases, an oligonucleotide ~30 nt in length is released from the duplex in complex with TFIIH. The remaining gap is filled in by the actions of DNA polymerase (Pol) and DNA ligase (Lig). Release of the excised oligonucleotide from TFIIH recycles TFIIH for new rounds of repair. The released 30-mer can then be targeted for degradation by nucleases or bound by RPA, which limits its degradation.

Figure 3. Roles of DNA repair intermediates in cell signaling. Processing of double-strand breaks by the MRN complex generates short oligonucleotides that remain associated with MRN and stimulate ATM kinase activity (left panel). Repair of 8-oxoguanine (8-oxoG) lesions by OGG1 during base excision repair leads to the formation of a stable OGG1–8-oxo-G complex that binds Ras and stimulates nucleotide exchange (middle panel). Nucleotide excision repair of thymine dimers releases oligonucleotides from the duplex that are initially in complex with TFIIH. This complex may activate an intracellular signaling pathway. After release from TFIIH, these oligonucleotides may bind RPA or other factors that may impact the cellular response to UV (right panel).