Fig. 2.
Major DNA repair pathways that are being targeted clinically using the SL approach. Cells rely on multiple mechanisms to repair DNA damage. DNA replication errors are repaired by MMR and DNA adducts and pyrimidine dimers resulting from UV and polycyclic aromatic hydrocarbons (PAHs) by NER. The repair of abasic sites and damaged bases and the removal of uracil as well as SSBs, caused by radiation, alkylating agents or reactive oxygen species (ROS), are performed by BER. DSBs that can arise from X-rays, antitumor agents or replication fork collapse are repaired by error-prone non-homologous end-joining (NHEJ) and error-free homologous recombination repair (HRR). The NHEJ pathways may be divided into canonical non-homologous end joining (c-NHEJ) or the alternative pathway for non-homologous end joining (alt-NHEJ). ICLs, which can be caused by chemotherapeutic agents (e.g., MMC and cisplatin) amongst others, covalently link both DNA strands preventing their separation during replication and transcription. In non-proliferating cells or during G1-phase this type of damage is recognized and removed by the NER pathway, followed by excision by XPF-ERCC1 and TLS. In replicating cells, DNA damage checkpoint is activated and damage is repaired by the FA/BRCA pathway. The other DNA duplex with a DSB may be finally repaired by multiple sub-pathways, being HRR the preferential one. Colored in red are the proteins for which selective drug inhibitors have been identified and have progressed to clinical trials. Figure created with BioRender