Telomere lengthening in telomerase-negative cells: the ends are coming together.
Telomeres are crucial for chromosomal stability and cell viability. Activation of telomerase, a specialized reverse transcriptase, is the predominant mechanism for maintaining telomere length and function in yeasts and human cells. Telomere maintenance is regarded as a key element in the immortalization of cells and hence in oncogenesis. Although more than 90% of all malignant tumors display telomerase activity, there appear to be alternatives to this mechanism. Alternative lengthening of telomeres (ALT) in the absence of telomerase has been described in various organisms and recently also in immortalized and transformed human cells. This article will discuss how ALT is detected and how it affects telomere morphology. It will review the frequency and relevance of ALT in in vitro immortalized cell lines, tumor-derived cell lines, and primary tumors. We have only begun to link mechanisms by means of which ALT may act in immortalized human cells to the growing knowledge about telomeres, and we can look forward to further fascinating insights into telomere biology. Our review will also emphasize recent advances in our understanding of the induction and repression of ALT and the demonstration of ALT in cancer cells in the light of new treatment strategies targeted against telomere maintenance mechanisms.