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. 2008 Nov;7(11):1783-6.
doi: 10.4161/cbt.7.11.6779. Epub 2008 Nov 4.

Deficiency of Bloom syndrome helicase activity is radiomimetic

David P Horowitz  1 , Ozlem Topaloglu, Yonggang Zhang, Fred Bunz
Affiliations

Deficiency of Bloom syndrome helicase activity is radiomimetic

David P Horowitz et al. Cancer Biol Ther. 2008 Nov.

Abstract

Bloom syndrome is caused by homozygous mutations in BLM, which encodes a RecQ DNA helicase. Patient-derived cells deficient in BLM helicase activity exhibit genetic instability--apparent cytogenetically as sister chromatid exchanges--and activated DNA damage signaling. In this report, we show that BLM-knockout colorectal cancer cells exhibited endogenous, ATM-dependent double-strand DNA break responses similar to those recently observed in Bloom syndrome patient-derived cells. Xenograft tumors established from BLM-deficient cancer cells were not radiosensitive, but exhibited growth impairment that was comparable to that of wild type tumors treated with a single, high dose of ionizing radiation. These results suggest that pharmacological inhibitors of BLM would have a radiomimetic effect and that transient inhibition of BLM activity might be a viable strategy for anticancer therapy.

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Figures

Figure 1
Figure 1
BLM-knockout colorectal cancer cells endogenously activate Chk2. (A) Whole cell lysates made from HCT116 and the BLM-knockout (BLM−/−) derivative cell lines were fractionated, transferred to PVDF membranes (Millipore) and probed with antibodies against phosphorylated forms of Chk1 (p-Chk1 S317, p-Chk1 S345), total Chk1, phosphorylated Chk2 (p-Chk2 T68) and total Chk2, as indicated. (B) Quantification of p-Chk2 T68 in untreated and IR-treated cells (1 h after treatment) was performed by near-infrared imaging. A single membrane was simultaneously probed with antibodies to p-Chk2 T68 and total Chk2, and developed with green and red IR dyes, respectively (see Materials and Methods). For each band, the signal from p-Chk2 T68 was normalized to the signal from total Chk2 protein. Plotted values are shown in arbitrary units (lower).
Figure 2
Figure 2
Elevated numbers of DSB response foci in BLM-knockout cells. γH2AX and phosphorylated forms of ATM (p-ATM S1981) and Chk2 (p-Chk2 T68) were visualized by immunofluorescence in untreated cells (-IR) and in cells 1 h after treatment with 7.5 Gy IR (+IR). Arrows indicate individual foci present in untreated BLM-knockout (BLM−/−) cells.
Figure 3
Figure 3
BLM-deficiency impairs growth of xenograft tumors. Established tumors derived from wild type HCT116 cells and BLM-knockout (BLM−/−) cells were treated with 7.5 Gy IR and compared with untreated controls. Each treatment and control group contained 5 or 6 tumor-bearing mice; each data point represents the results of two independent experiments.
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