Non‐telomerase telomere maintenance in human cells (97.2)

Abstract

Although it has recently been demonstrated that telomeres can be lengthened by a non‐telomerase mechanism (i.e., Alternative Lengthening of Telomeres; ALT) in normal mouse tissues, we have learnt most about ALT in mammalian cells from the study of in vitro‐immortalized and tumor‐derived human cell lines. Apart from its intrinsic biological interest, it is important to understand ALT because ~10% of human cancers utilize it to avoid senescence, and some of the tumor types where ALT is common, such as soft tissue sarcomas and astrocytic brain tumors, are currently difficult to treat. Loss of normal ATRX or DAXX function contributes to, but is insufficient for the upregulation of ALT in many cancers and cell lines. An increased non‐canonical telomeric repeat sequence content may also foster increased levels of ALT activity by decreasing shelterin binding sites. ALT involves synthesis of new telomeric DNA via recombination‐mediated copying of existing telomeric sequences. The template may be the DNA of another telomere or a more proximal region of the telomere that is being lengthened. There is a tight correlation between the level of C‐circles, i.e., extrachromosomal circles of partially double‐stranded telomeric DNA with an intact C‐rich strand and an incomplete G‐rich strand, and ALT activity. We are therefore using a C‐circle assay to identify genes/ proteins involved in the ALT mechanism.