Nucleotide excision repair lesion removal with

Crosslinks result from the reaction of a bifunctional electrophilic species with DNA bases and imply a covalent link between two adjacent DNA strands which inhibits DNA replication. Primary targets within bases are N7 and 06 in guanine and N3 in cytosine. The initial lesions are removed by the suicide enzyme alkyltrans-ferase, whereas nucleotide excision repair is needed for frilly established crosslinks. 

FIGURE 25-24 Nucleotide-excision repair in E. coli and humans. The general pathway of nucleotide-excision repair is similar in all organisms. (J) An excinuclease binds to DNA at the site of a bulky lesion and cleaves the damaged DNA strand on either side of the lesion. (2) The DNA segment—of 13 nucleotides (13 mer) or 29 nucleotides (29 mer)—is removed with the aid of a helicase. (3) The gap is filled in by DNA polymerase, and the remaining nick is sealed with DNA ligase. 

Notably, photodimers of the cyclobutane type are cleaved by irradiation with far-UV light (240 nm) with a quantum yield of almost unity by way of the so-called [2+2] cycloreversion reaction. In living cells, dimer lesions can be repaired by the nucleotide excision repair pathway, which is based on the excision of a small piece of DNA around the lesion. Lesions not removed from the genome lead to cell death or mutagenesis. 

Utilising a reversion assay in Salmonella enterica, Prieto et al reported an increased frequency of point mutations following bile-salt exposure. Mutations were predominantly nucleotide substitutions (GC to AT transitions) and -1 frameshift mutations.The frameshifts were dependent on SOS induction and linked to the activity of DinB polymerase (Pol IV). The authors proposed that the GC to AT transitions stimulated by bile, could have arisen from oxidative processes giving rise to oxidised cytosine residues. Consistent with this hypothesis, the authors demonstrated that strains of S. enterica-lacking enzymes required for base-excision repair (endonuclease III and exonuclease IV) and the removal of oxidised bases, demonstrated increased bile-acid sensitivity compared with competent strains. In another study using E. coli, resistance to the DNA-damaging effects of bile was associated with Dam-directed mismatch repair, a pathway also involved with the repair of oxidative DNA lesions. ... 

One of the lesions removed by nucleotide excision is the thymine photodimer.705 In the fission yeast S. pombe an alternative excision repair system, specialized for removal of thymine dimers and 6-4 photoproducts (Chapter 23), produces two-nucleotide gaps with 3 -OH and 5 -phospho-group ends.702/705a Alternative NER pathways are also employed by bacteria.705b... 

---