The ability of most cancer cells to grow indefinitely relies on the enzyme telomerase and its recruitment to telomeres. The molecular details of the pathways governing human telomerase recruitment are not well understood, but this understanding may lead to potential avenues to block telomerase action as a cancer therapeutic. In human cells recruitment depends on the Cajal body RNA chaperone TCAB1 binding to the RNA subunit of telomerase (hTR). We demonstrate that coilin, an essential structural component of nuclear Cajal bodies, is required for endogenous telomerase recruitment to telomeres but that overexpression of telomerase can compensate for Cajal body absence. In contrast, recruitment of telomerase was sensitive to levels of TCAB1 and this was not rescued by overexpression of telomerase. Thus, although Cajal bodies are important for recruitment, TCAB1 has an additional role in this process that is independent of these structures: TCAB1 localises to telomeres in a telomerase-dependent but Cajal body-independent manner (1). Our results demonstrate that telomerase has multiple independent requirements for recruitment to telomeres, and that the function of TCAB1 is to directly transport telomerase to telomeres.
Telomerase recruitment in yeast involves the homologue of the DNA damage response protein ATM, but in mice this does not appear to be the case (2). We assessed the role of ATM and other PIKK proteins as well as some of their interacting partners in endogenous telomerase recruitment. Expression of ATM, DNA-PKcs, and SMG1 were required for full recruitment of telomerase to telomeres. Tests of the PIKK interacting partner proteins indicate that expression of some of these proteins are required for full recruitment. These data provide evidence for the requirement of the DNA damage response proteins in telomerase recruitment in immortal human cells.