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Cell Mol Life Sci. 2010 Nov;67(21):3683-97. doi: 10.1007/s00018-010-0492-6. Epub 2010 Aug 21.

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

Author information

1
Department of Pharmacological Sciences, Stony Brook University, Stony Brook, NY 11794-3400, USA.

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.

PMID:
20730555
PMCID:
PMC3732395
DOI:
10.1007/s00018-010-0492-6
[Indexed for MEDLINE]
Free PMC Article

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