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7 Telomerase-independent Maintenance of Mammalian Telomeres

Axel A. Neumann, Roger R. Reddel


In most normal somatic cells, telomeres shorten with every cell division because of the end replication problem (Harley et al. 1990). The cumulative loss of telomeric DNA sequence is thought to act as a “mitotic clock” that limits the replicative potential of cells. Prevention of continued telomere loss by activation of a telomere maintenance mechanism appears to be essential for the development of most human cancers. The majority of cancers and cancer cell lines maintain their telomeres via activity of the telomerase ribonucleoprotein holoenzyme complex (Kim et al. 1994). Some immortalized mammalian cell lines and tumors, however, are able to maintain their telomere lengths over many population doublings in the absence of telomerase activity, indicating the existence of one or more non-telomerase-based mechanisms for telomere maintenance that have been termed alternative lengthening of telomeres (ALT) (Bryan and Reddel 1997). So far, ALT has only been detected in anomalous situations, such as human cancers and immortalized cell lines, telomerase-null mouse cell lines and tumors, and an immortalized Indian muntjac cell line (Bryan et al. 1995Bryan et al. 1997a; Hande et al. 1999; Niida et al. 2000; Zou et al. 2002; Chang et al. 2003). However, indirect evidence was obtained for in vivo ALT activity in splenocytes from late-generation telomerase-null mice, which showed reduced germinal center formation after immunization, but, surprisingly, had elongated telomeres (Herrera et al. 2000). Detailed analyses of telomere length fluctuations in telomerase-null embryonic fibroblasts were also consistent with an ALT-like recombinational telomere lengthening mechanism (Hande et al. 1999). Here we...

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