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Interstrand Crosslink Repair as a Target for HDAC Inhibition

Teodora Nikolova1, Nicole Kiweler1, Oliver H Krämer1

  • 1Institute of Toxicology, University Medical Center, Obere Zahlbacher Strasse 67, 55131 Mainz, Germany.

Trends in Pharmacological Sciences
|July 9, 2017
PubMed

Insights

DNA interstrand crosslinks (ICLs) trigger cell death, but tumors repair them. Histone deacetylase inhibitors (HDACi) block repair pathways, making cancer cells more sensitive to ICL-inducing drugs.

Area of Science:

  • Molecular Biology
  • Cancer Biology
  • Pharmacology

Background:

  • DNA interstrand crosslinks (ICLs) covalently bind DNA strands, halting replication and transcription.
  • ICLs activate DNA damage responses (DDR) and can trigger cell death, making ICL-inducing drugs effective cancer therapies.
  • Tumors possess repair mechanisms to counteract ICLs, often involving enzymatic pathways and post-translational modifications like acetylation/deacetylation.

Purpose of the Study:

  • To elucidate the mechanism of DNA interstrand crosslink repair.
  • To identify targets of histone deacetylase inhibitors (HDACi) within the ICL repair pathway.
  • To explain how HDACi sensitize cancer cells to ICL-inducing agents.

Main Methods:

  • Review of ICL repair pathways.
  • Analysis of histone deacetylase (HDAC) functions in DNA repair.
  • Discussion of the role of HDAC inhibitors (HDACi) in cancer therapy.

Main Results:

  • Histone deacetylases (HDACs) regulate DNA repair proteins involved in ICL removal.
  • HDACs influence chromatin accessibility, impacting DNA repair efficiency.
  • HDAC inhibitors (HDACi) target key components of the ICL repair network.

Conclusions:

  • HDACs play a critical role in the enzymatic machinery that repairs DNA interstrand crosslinks.
  • HDAC inhibitors represent a promising strategy to overcome tumor resistance to ICL-inducing chemotherapy.
  • Targeting HDACs can enhance the efficacy of cancer treatments that rely on DNA damage induction.
Keywords:
DNA double-strand breaksHDACchloroethylnitrosoureashomologous recombinationinterstrand crosslink repairplatinum compounds

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