Effect of chemotherapeutic drugs on telomere length and telomerase activity

Abstract

Telomeres are specialized nucleoproteic complexes localized at the ends of eukaryotic chromosomes, that maintain their stability and integrity. They protect chromosome ends from fusion and from being recognized as sites of DNA damage, i.e., they distinguish natural DNA ends from DNA ends resulting from breakage events. In mammalian cells, telomeres consist of tandem arrays of the hexanucleotide TTAGGG, oriented 5′ to 3′ towards the end of the chromosomes and associated proteins (the so-called “shelterin” complex), and a large non-coding RNA (named TERRA) which forms an integral component of telomeric heterochromatin. Telomere length is maintained by a dynamic process of telomere shortening and lengthening. Shortening can occur due to nucleolytic degradation and incomplete DNA replication due to the inability of lagging strand synthesis to completely replicate chromosomal ends (i.e., the “end replication problem”), whereas lengthening is primarily accomplished by the action of the enzyme telomerase and occasionally by the so-called Alternative Lengthening of Telomeres (“ALT”) mechanism, which involves homologous recombination. The maintenance of telomere function is crucial for genomic stability and cell viability. Cells respond to dysfunctional telomeres by undergoing senescence, cell death, or genomic instability. Since telomeres play a fundamental role in maintaining chromosomal/genomic stability and telomerase activity and telomere lengthening play a key role in cancer development and progression, a proper knowledge of the effects of chemotherapeutic drugs on telomere length and telomerase activity in normal as well as tumor cells is of great importance to understand the genomic instability associated with chemotherapy regimens. Therefore, in this review we will summarize our current knowledge concerning the main data available about the effects of chemotherapeutic drugs on telomere length and telomerase activity in mammalian cells.