Arsenic inhibition of telomerase transcription leads to genetic instability
Wen-Chien Chou, … , Constance A. Griffin, Chi V. Dang
Wen-Chien Chou, … , Constance A. Griffin, Chi V. Dang
Published November 15, 2001
Citation Information: J Clin Invest. 2001;108(10):1541-1547. https://doi.org/10.1172/JCI14064.
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Article

Arsenic inhibition of telomerase transcription leads to genetic instability

Abstract

Arsenic is effective in the treatment of acute promyelocytic leukemia. Paradoxically, it is also carcinogenic. In the process of elucidating a mechanism of arsenic resistance in a leukemia cell line, NB4, we discovered that arsenic exposure causes chromosomal abnormalities, with a preponderance of end-to-end fusions. These chromosomal end fusions suggested that telomerase activity may be inhibited by arsenic. We found that arsenic inhibits transcription of the hTERT gene, which encodes the reverse transcriptase subunit of human telomerase. This effect may in part be explained by decreased c-Myc and Sp1 transcription factor activities. Decreased telomerase activity leads to chromosomal end lesions, which promote either genomic instability and carcinogenesis or cancer cell death. These phenomena may explain the seemingly paradoxical carcinogenic and antitumor effects of arsenic.

Authors

Wen-Chien Chou, Anita L. Hawkins, John F. Barrett, Constance A. Griffin, Chi V. Dang

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Figure 1

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Chromosomal abnormalities and telomerase activity of NB4 cells treated w...
Chromosomal abnormalities and telomerase activity of NB4 cells treated with arsenic. (a) A representative entire metaphase from NB4 cells treated with arsenic at 0.75 μM for 3 weeks. The arrows indicate dicentric fusion chromosomes. (b) Representative dicentric chromosomal fusions as well as other abnormal fused chromosomes and fragments from cells treated with arsenic at 0.75 μM for 3 weeks. (c) Southern blot of digested genomic DNA from NB4 (left) and HeLa cells (right) showed decreased telomere length after arsenic exposure. Lane 1: untreated NB4 cells; lanes 2−4: 0.25 μM arsenic for 4, 5, and 6 weeks, respectively. Lane 5: untreated HeLa cells; lanes 6 and 7: 1 μM arsenic for 3 and 4 weeks, respectively. (d) Dicentric chromosome after FISH with a telomere-specific probe. Arrows indicate centromeres. FISH signals are clearly visible at both ends of the fusion chromosome. Among 16 fusions studied, no hybridization is seen between the centromeres where fusion occurred. In contrast, 95−97% of chromosome ends of a normal lymphocyte control display intense signal (data not shown). (e) Telomerase activity of NB4 cells treated with arsenic. Pooled NB4 cells and independently isolated subclones showed dramatically decreased telomerase activity after 8 days of 0.75 μM arsenic. The internal control represents a band that should appear in every TRAP assay to ensure a reliable PCR reaction. Because of competition of components, higher telomerase activities result in fainter internal control bands.