for the existence of telomeric G-quadruplex structures in vivo, and for their role in telomere replication, comes from studies in ciliates (Paeschke et al, 2008). Understanding the possible role of these structures in telomere length regulation, or DNA metabolism in general, remains a difﬁcult task (Johnson et al, 2008). Studies on the maturation of human telomerase are begin- ning to reveal new factors that have a function in telomerase assembly (reviewed in Collins, 2006). The human telomerase holoenzyme minimally contains the catalytic subunit (TERT), the telomerase RNA (TERC), and an RNA ‘H/ACA box’- binding protein called dyskerin (Cohen et al, 2007). In an exciting recent development, Artandi and co-workers have isolated a novel protein, TCAB1 (telomerase and Cajal body protein 1), based on its interaction with dyskerin, which associates with Cajal bodies and which might be important for delivering telomerase to telomeres (Venteicher et al, 2009). A role for Cajal bodies in allowing the association of telomerase with telomeres in S phase has recently been recognized (Jady et al, 2006; Tomlinson et al, 2006), and the interaction of telomerase with Cajal bodies appears to be important for telomerase action at chromosome ends (Cristofari et al, 2007). Signiﬁcantly, TCAB1, which associates with active telomerase, is required for telomerase association both with Cajal bodies and with telomeres, and for telomere repeat synthesis at chromosome ends. Thus, the emerging view is that the mammalian telomerase enzyme has hijacked a Cajal body pathway for spliceosomal RNA maturation as part of a mechanism to deliver the telomerase RNP in an active form to telomeres. Why Cajal bodies might function as ‘delivery stations’ to allow efﬁcient recruitment of telomerase to telomeres is presently unclear, and other possibilities (e.g. that Cajal bodies facilitate assembly of an ‘active’ enzyme capable of functioning in the context of native DNA ends) cannot at present be ruled out (Venteicher and Artandi, 2009). Finally, though telomeres have been long thought to be transcriptionally silent chromosome domains, it is now clear that telomere repeats are indeed transcribed, in organisms as diverse as yeast and human (Azzalin et al, 2007; Luke et al, 2008; Schoeftner and Blasco, 2008). The potential role of telomeric RNA, dubbed ‘TERRA’, as well as that of telomeric chromatin structure in homeostatic regulation of the telomer- References Adams AK, Holm C (1996) Speciﬁc DNA replication mutations affect telomere length in Saccharomyces cerevisiae. Mol Cell Biol 16: 4614–4620 Amiard S, Doudeau M, Pinte S, Poulet A, Lenain C, Faivre- Moskalenko C, Angelov D, Hug N, Vindigni A, Bouvet P, Paoletti J, Gilson E, Giraud-Panis MJ (2007) A topological me- chanism for TRF2-enhanced strand invasion. Nat Struct Mol Biol 14: 147–154 Arneric M, Lingner J (2007) Tel1 kinase and subtelomere-bound Tbf1 mediate preferential elongation of short telomeres by telo- merase in yeast. EMBO Rep 8: 1080–1085 Aylon Y, Kupiec M (2005) Cell cycle-dependent regulation of double-strand break repair: a role for the CDK. Cell Cycle 4: 259–261 Azzalin CM, Reichenbach P, Khoriauli L, Giulotto E, Lingner J (2007) Telomeric repeat containing RNA and RNA surveillance factors at mammalian chromosome ends. Science 318: 798–801 & 2009 European Molecular Biology Organization Feedback control of telomere length D Shore and A Bianchi ase pathway are both exciting open questions, and the reader is referred to the accompanying reviews (Bu¨ hler and Gasser, 2009; Luke and Lingner, 2009; Schoeftner and Blasco, 2009) for detailed discussions of these topics. Concluding remarks In little over 20 years since the discovery of the telomerase enzyme, considerable progress has been made in unravelling the molecular mechanisms underlying the control of this unique mode of chromosome end replication. The general picture that has emerged is one in which the protein complexes assembled on telomere repeat sequences have a dual function, on the one hand assisting the recruitment and activation of telomerase enzyme at telomeres, yet on the other hand colla- borating in what seem to be multiple modes of negative feed- back on telomerase action that serve to maintain telomere repeat length homeostasis. One striking and recurrent observa- tion from this work is the connection between telomerase- based replication and the DNA damage response, both at the level of the proteins involved and the enzymatic and structural transitions of the telomeric DNA itself. In fact, telomeres in an extendable state bear a striking resemblance to DNA DSBs, and we still lack a clear understanding of how the cell can so faithfully channel these two related structures towards the appropriate ‘repair’ pathways. Furthermore, regulation of telo- merase action has multiple connections to conventional DNA replication, both at the level of the DNA polymerases them- selves and control of DNA replication initiation at telomere- proximal origins, all of which need to be more clearly under- stood. These and other questions constitute signiﬁcant chal- lenges for the ﬁeld in the coming years. Considering the recent and unexpected discovery of telomeric RNA, we should antici- pate additional surprises as a diverse set of telomere length regulatory mechanisms come into better focus. Acknowledgements Work in the Shore laboratory is supported by grants from the Swiss National Fund (grant 31003A116716), from the Swiss National Fund ‘Frontiers in Genetics’ National Centre, and from the Canton of Geneva. Work in the Bianchi laboratory is funded by the Medical Research Council. We apologize to those whose work could not be cited or discussed due to space limitations. Bae NS, Baumann P (2007) A RAP1/TRF2 complex inhibits non- homologous end-joining at human telomeric DNA ends. Mol Cell 26: 323–334 Baumann P, Cech TR (2001) Pot1, the putative telomere end-binding protein in ﬁssion yeast and humans. Science 292: 1171–1175 Bhattacharyya MK, Lustig AJ (2006) Telomere dynamics in genome stability. Trends Biochem Sci 31: 114–122 Bianchi A, Negrini S, Shore D (2004) Delivery of yeast telomerase to a DNA break depends on the recruitment functions of Cdc13 and Est1. Mol Cell 16: 139–146 Bianchi A, Shore D (2007a) Early replication of short telomeres in budding yeast. Cell 128: 1051–1062 Bianchi A, Shore D (2007b) Increased association of telomerase with short telomeres in yeast. Genes Dev 21: 1726–1730 Bianchi A, Shore D (2008) How telomerase reaches its end: me- chanism of telomerase regulation by the telomeric complex. Mol Cell 31: 153–165 The EMBO Journal VOL 28 | NO 16 | 2009 2319