Targeted radiosensitization of cells expressing truncated DNA polymerase {beta}

Cancer Res. 2010 Nov 1;70(21):8706-14. doi: 10.1158/0008-5472.CAN-09-3901. Epub 2010 Oct 26.


Ionizing radiation (IR) is an effective anticancer treatment, although failures still occur. To improve radiotherapy, tumor-targeted strategies are needed to increase radiosensitivity of tumor cells, without influencing normal tissue radiosensitivity. Base excision repair (BER) and single-strand break repair (SSBR) contribute to the determination of sensitivity to IR. A crucial protein in BER/SSBR is DNA polymerase β (polβ). Aberrant polβ expression is commonly found in human tumors and leads to inhibition of BER. Here, we show that truncated polβ variant (polβ-Δ)-expressing cells depend on homologous recombination (HR) for survival after IR, indicating that a considerable fraction of polβ-Δ-induced lesions are subject to repair by HR. Increased sensitization was found not to result from involvement in DNA-dependent protein kinase-dependent nonhomologous end joining, the other major double-strand break repair pathway. Caffeine and the ATM inhibitor Ku55933 cause polβ-Δ-dependent radiosensitization. Consistent with the observed HR dependence and the known HR-modulating activity of ATM, polβ-Δ-expressing cells showed increased radiosensitization after BRCA2 knockdown that is absent under ATM-inhibited conditions. Our data suggest that treatment with HR modulators is a promising therapeutic strategy for exploiting defects in the BER/SSBR pathway in human tumors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Ataxia Telangiectasia Mutated Proteins
  • BRCA2 Protein / antagonists & inhibitors
  • BRCA2 Protein / metabolism
  • Blotting, Western
  • Cell Cycle Proteins / antagonists & inhibitors
  • Cell Cycle Proteins / metabolism
  • Chromones / pharmacology*
  • DNA Damage / drug effects
  • DNA Polymerase beta / genetics
  • DNA Polymerase beta / metabolism*
  • DNA Repair / radiation effects
  • DNA-Binding Proteins / antagonists & inhibitors
  • DNA-Binding Proteins / metabolism
  • Humans
  • Lung Neoplasms / drug therapy
  • Lung Neoplasms / enzymology*
  • Lung Neoplasms / radiotherapy*
  • Morpholines / pharmacology*
  • Protein Serine-Threonine Kinases / antagonists & inhibitors
  • Protein Serine-Threonine Kinases / metabolism
  • RNA, Messenger / genetics
  • RNA, Small Interfering / pharmacology
  • Radiation Tolerance / drug effects*
  • Radiation, Ionizing
  • Recombination, Genetic / drug effects*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Tumor Cells, Cultured
  • Tumor Stem Cell Assay
  • Tumor Suppressor Proteins / antagonists & inhibitors
  • Tumor Suppressor Proteins / metabolism


  • 2-(morpholin-4-yl)benzo(h)chromen-4-one
  • BRCA2 Protein
  • Cell Cycle Proteins
  • Chromones
  • DNA-Binding Proteins
  • Morpholines
  • RNA, Messenger
  • RNA, Small Interfering
  • Tumor Suppressor Proteins
  • ATM protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • Protein Serine-Threonine Kinases
  • DNA Polymerase beta