Interstrand Crosslink Repair as a Target for HDAC Inhibition

Teodora Nikolova*, Nicole Kiweler, Oliver H. Krämer

*Corresponding author for this work

Research output: Contribution to journalReview articlepeer-review

37 Citations (Scopus)

Abstract

DNA interstrand crosslinks (ICLs) covalently connect complementary DNA strands. Consequently, DNA replication and transcription are hampered, DNA damage responses (DDR) are initiated, and cell death is triggered. Therefore, drugs inducing ICLs are effective against rapidly growing cancer cells. However, tumors engage a complicated enzymatic machinery to repair and survive ICLs. Several factors, including the post-translational acetylation/deacetylation of lysine residues within proteins, control this network. Histone deacetylases (HDACs) modulate the expression and functions of DNA repair proteins which remove ICLs and control the accessibility of chromatin. Accordingly, histone deacetylase inhibitors (HDACi) are small, pharmacologically and clinically relevant molecules that sensitize cancer cells to ICL inducers. We discuss the mechanism of ICL repair and targets of HDACi within this pathway.

Original languageEnglish
Pages (from-to)822-836
Number of pages15
JournalTrends in Pharmacological Sciences
Volume38
Issue number9
DOIs
Publication statusPublished - Sep 2017
Externally publishedYes

Keywords

  • chloroethylnitrosoureas
  • DNA double-strand breaks
  • HDAC
  • homologous recombination
  • interstrand crosslink repair
  • platinum compounds

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