Figure 4. The four major pathways for the repair of DNA damaged by anticancer drugs.

BER: in the initial step the adducted base is excised off the DNA backbone, leaving an abasic site that is sequentially processed by a number of enzymes (see Figure 5). NER: the lesion, which generally has a helix distorting effect, is initially recognized by proteins that then recruit endonucleases that cut a segment out of DNA including the lesion. The gap is filled in by DNA polymerase and the ends ligated. Direct reversal: the alkyl lesion is directly transferred from the DNA nucleobases to the repair protein in a one-step suicide reaction. ICL repair: in the initial step the crosslink is recognized by enzymes associated with NER and then one end of the crosslink is unhooked by endonucleases. The remaining lesion (shown in the figure) is then bypassed by a translesion polymerase. The remaining monofunctional lesion is then processed as in NER. If the repair occurs during DNA replication, potential errors made during the error-prone bypass step can be corrected by homologous recombination in which a strand from the sister chromatid serves as an undamaged template.

BER: Base excision repair; ICL: Interstrand crosslink; NER: Nucleotide excision repair; X: Monofunctional or crosslinked lesion.