Using synthetic DNA interstrand crosslinks to elucidate repair pathways and identify new therapeutic targets for cancer chemotherapy

Abstract

Many cancer chemotherapic agents form DNA interstrand crosslinks (ICLs), extremely cytotoxic lesions that form covalent bonds between two opposing DNA strands, blocking DNA replication and transcription. However, cellular responses triggered by ICLs can cause resistance in tumor cells, limiting the efficacy of such treatment. Here we discuss recent advances in our understanding of the mechanisms of ICL repair that cause this resistance. The recent development of strategies for the synthesis of site-specific ICLs greatly contributed to these insights. Key features of repair are similar for all ICLs, but there is increasing evidence that the specifics of lesion recognition and synthesis past ICLs by DNA polymerases are dependent upon the structure of ICLs. These new insights provide a basis for the improvement of antitumor therapy by targeting DNA repair pathways that lead to resistance to treatment with crosslinking agents.

Hyphenated techniques as tools for speciation analysis of metal-based pharmaceuticals: developments and applications

“…(i) Repair of DNA-platinum lesion [41,42] (ii) Changes to drug transport and distribution [43] (iii) Inactivation of the drug through interactions with natural occurring antidotes (e.g., glutathione) [44] The latter mechanism involves a ligand substitution reaction with the platinum center. Attenuating this substitution reaction should give a compound with a reduced susceptibility to this mechanism.…”

DNA Interstrand Cross-Linking Agents and their Chemotherapeutic Potential

“…The repair mechanism has been frequently reviewed because of rapid advances in this sector or authors attempt to provide details of some particular step or bring a different point of view on this process. The most recent reviews are focused specifically on a description of a role of proteins involved in the repairing [65][66][67][68][69], selected processes involved in the mechanism [70][71][72], repair of DNA during S phase of the cell cycle [73], initiation of ICL repair process [74], repairing in context of finding new targets in chemotherapy [75][76][77] or overall summary of repairing [61,[78][79][80]. In the following part we briefly summarize the current state of knowledge to demonstrate the difficulty and complexity of the ICL repairing in the context of actual possibilities for chemotherapeutic treatment.…”

SiDNA and Other Tools for the Indirect Induction of DNA Damage Responses

“…Nucleotide-excision repair, homologous recombination repair, the Fanconi anemia repair pathway, MMR and translesion synthesis have all been shown to participate in ICL repair. Oligonucleotides containing synthetic ICLs are a valuable tool for the study of ICL repair (Guainazzi & Scharer, 2010). The advantage of such molecules over cell treatment with a cross-linking agent is that it is possible to study the components involved in the repair of specific interstrand crosslink products one at a time.…”