Multi-Author Review

Cellular and Molecular Life Sciences

, Volume 67, Issue 21, pp 3683-3697

First online:

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

  • Angelo GuainazziAffiliated withDepartments of Pharmacological Sciences, Chemistry 619, Stony Brook University
  • , Orlando D. SchärerAffiliated withDepartments of Pharmacological Sciences and Chemistry, Chemistry 619, Stony Brook University Email author 

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Abstract

Many cancer chemotherapeutic 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.

Keywords

Interstrand crosslinks Cancer chemotherapy DNA repair Cisplatin Nitrogen mustards