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Review
. 2018 Dec;64(6):1177-1181.
doi: 10.1007/s00294-018-0836-6. Epub 2018 Apr 16.

How long does telomerase extend telomeres? Regulation of telomerase release and telomere length homeostasis

Kazunori Tomita  1
Affiliations
Review

How long does telomerase extend telomeres? Regulation of telomerase release and telomere length homeostasis

Kazunori Tomita. Curr Genet. 2018 Dec.

Abstract

Telomerase, the enzyme that replenishes telomeres, is essential for most eukaryotes to maintain their generations. Telomere length homeostasis is achieved via a balance between telomere lengthening by telomerase, and erosion over successive cell divisions. Impaired telomerase regulation leads to shortened telomeres and can cause defects in tissue maintenance. Telomeric DNA is composed of a repetitive sequence, which recruits the protective protein complex, shelterin. Shelterin, together with chromatin remodelling proteins, shapes the heterochromatic structure at the telomere and protects chromosome ends. Shelterin also provides a foothold for telomerase to be recruited and facilitates telomere extension. Such mechanisms of telomere recruitment and activation are conserved from unicellular eukaryotes to humans, with the rate of telomere extension playing an important role in determining the length maintained. Telomerase can be processive, adding multiple telomeric repeats before dissociating. However, a question remains: how does telomerase determine the number of repeats to add? In this review, I will discuss about how telomerase can monitor telomere extension using fission yeast as a model. I propose a model whereby the accumulation of the Pot1 complex on the synthesised telomere single-strand counteracts retention of telomerase via chromatin proteins and the similar system may be conserved in mammals.

Keywords: Chromatin; Processivity; Replication; Shelterin; Telomerase; Telomere length homeostasis.

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Figures

Fig. 1
Fig. 1
Proposed model for telomere extension and telomerase turn over in fission yeast. a Non-extendible conformation of shelterin stabilises 3′ end of the telomere. Shelterin is comprised for Pot1, Tpz1, Ccq1, Poz1, Rap1 and Taz1 that binds to the double-stranded telomeric DNA. Ccq1 may interact with SHREC. Est1 can be recruited to Ccq1 when it becomes phosphorylated. b The interaction between Ccq1 and Est1 results in release of SHREC from Ccq1 and the telomere becomes an ‘extendible state’ (dissolution of the shelterin bridge; Poz1 is dissociated from Rap1 as an example in this diagram). c Trt1 associates with Tpz1 and Ccq1 to promote telomerase activation. The RNA template of TER1 hybridises with 3′ end of the telomere overhang (Arrow: DNA/RNA hybrid formation). Taz1, Rap1 and Poz1 are omitted from the diagram. d Stabilised telomerase adds telomeric repeats to the G-rich strand. RPA binds to the synthesised DNA. e The Pot1-Tpz1-Ccq1 complex replaces RPA. Ccq1 may recruit SHREC. f Accumulation of the Pot1-Tpz1-Ccq1-SHREC complex on the telomere overhang releases the telomerase-associated Ccq1 complex from the telomere. The Pot1 complex at the 3′ end of the G-overhang can recruit telomerase (back to a)
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