Targeting the nucleotide excision repair pathway for therapeutic applications

N. S. Gavande, P. S. VanderVere-Carozza, K. S. Pawelczak, John Turchi

Research output: Chapter in Book/Report/Conference proceedingChapter

4 Scopus citations

Abstract

The NER (nucleotide excisions repair) pathway involves a coordinated series of interactions that enable the recognition and repair of bulky adduct DNA damage. Our understanding of the NER pathway has been significantly enhanced by the identification, characterization, and molecular analysis of cells and tissue obtained from individuals with Xeroderma pigmentosum. Reconstitution of the pathway in vitro has also enabled the molecular interactions to be interrogated in great detail. Finally, high-resolution structural analysis of many of the components provides a molecular basis for many of the interactions. Together, this convergence of knowledge provides a framework for efforts to disrupt the NER pathway to aid in the treatment of human disease, most notably cancer. It has been suggested all cancers display some defect in DNA repair and it has been demonstrated that the ability of cancer cells to repair therapeutically induced DNA damage impacts therapeutic efficacy. Although initial studies involving agents speculated to inhibit NER languished and were plagued by lack of specificity and a defined mechanism of action, more recent approaches to exploit synthetic lethal interactions and develop high-affinity chemical inhibitors have proven considerably more effective. In this chapter, we will highlight recent advances and discuss previous failures in targeting NER to pave the way for future DNA repair targeted agents and their use in cancer therapy.

Original languageEnglish (US)
Title of host publicationDNA Repair in Cancer Therapy: Molecular Targets and Clinical Applications: Second Edition
PublisherElsevier Inc.
Pages135-150
Number of pages16
ISBN (Print)9780128035825
DOIs
StatePublished - Jun 21 2016

Keywords

  • Chemical biology
  • Cisplatin
  • DNA damage
  • Inhibitors
  • Nucleotide excision repair
  • Replication protein A
  • Xeroderma pigmentosum

ASJC Scopus subject areas

  • Medicine(all)

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  • Cite this

    Gavande, N. S., VanderVere-Carozza, P. S., Pawelczak, K. S., & Turchi, J. (2016). Targeting the nucleotide excision repair pathway for therapeutic applications. In DNA Repair in Cancer Therapy: Molecular Targets and Clinical Applications: Second Edition (pp. 135-150). Elsevier Inc.. https://doi.org/10.1016/B978-0-12-803582-5.00005-X