Cellular and Molecular Life Sciences

, Volume 67, Issue 21, pp 3683–3697

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

Multi-Author Review

DOI: 10.1007/s00018-010-0492-6

Cite this article as:
Guainazzi, A. & Schärer, O.D. Cell. Mol. Life Sci. (2010) 67: 3683. doi:10.1007/s00018-010-0492-6

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 crosslinksCancer chemotherapyDNA repairCisplatinNitrogen mustards

Abbreviations

ICL

Interstrand crosslink

NM

Nitrogen mustards

NER

Nucleotide excision repair

CENU

Chloro nitroso urea

MMC

Mitomycin C

FA

Fanconi anemia

HR

Homologous recombination

TLS

Translesion synthesis

Copyright information

© Springer Basel AG 2010

Authors and Affiliations

  1. 1.Departments of Pharmacological Sciences, Chemistry 619Stony Brook UniversityStony BrookUSA
  2. 2.Departments of Pharmacological Sciences and Chemistry, Chemistry 619Stony Brook UniversityStony BrookUSA