Targeted radiosensitization of cells expressing truncated DNA polymerase {beta}.
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.
Division of Experimental Therapy, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
Sari
S
Neijenhuis
Manon
M
Verwijs-Janssen
Lenie J
LJ
van den Broek
Adrian C
AC
Begg
Conchita
C
Vens
D064007:Ataxia Telangiectasia Mutated Proteins; D024682:BRCA2 Protein / Q000037:antagonists & inhibitors / Q000378:metabolism; D015153:Blotting, Western; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D002867:Chromones / Q000494:pharmacology*; D004249:DNA Damage / Q000187:drug effects; D019951:DNA Polymerase beta / Q000235:genetics / Q000378:metabolism*; D004260:DNA Repair / Q000528:radiation effects; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000532:radiotherapy*; D009025:Morpholines / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000494:pharmacology; D011836:Radiation Tolerance / Q000187:drug effects*; D011839:Radiation, Ionizing; D011995:Recombination, Genetic / Q000187:drug effects*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D014410:Tumor Stem Cell Assay; D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism
C479235:2-(morpholin-4-yl)benzo(h)chromen-4-one; D024682:BRCA2 Protein; D018797:Cell Cycle Proteins; D002867:Chromones; D004268:DNA-Binding Proteins; D009025:Morpholines; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases; D019951:DNA Polymerase beta