Arsenic and old telomeres

Telomeres, the simple repeat structures that cap each end of chromosomes, are required for chromosomal stability both in the short and long run. Over the course of one or more generations, a gradual loss of sequence from the chromosomes, occurring at each cell division, would eventually erase crucial genetic information from the genome if the cell had no mechanism to rebuild the telomere. In addition, because short or missing telomeres predispose chromosomes to fuse and create abnormal structures that cannot be assorted properly during mitosis, their disappearance could lead otherwise normal cells to undergo apoptosis?or, in some cases, to become transformed and generate tumors. Telomerase, the enzyme responsible for adding telomere repeats to the end of each chromosome, prevents both gradual chromosomal degradation and sudden loss of normal cell function. However, because telomerase activation is one means by which cancer cells escape normal growth control, this enzyme must be tightly regulated, and there has been considerable interest in blocking its function or expression. Now Chou et al. report that one of the oldest known agents in medical history has just such an effect. They show here that the toxic metal arsenic, which has proved helpful in controlling otherwise intractable leukemias, blocks transcription of one of the telomerase subunits in an apparently specific fashion. Treating tumor cells with moderate levels of arsenic mimics the effect seen in cells lacking telomerase, including shortening of the telomeres and the accumulation of structurally abnormal chromosomes. The transcriptional silencing of the telomerase subunit by arsenic is not fully understood, but it appears to involve the oxidative inhibition of the transcription factor Sp1.

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