Recruitment of Telomerase RNP to the Telomeric Chromosome End

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Reaction [binding]
Homo sapiens
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Studies in yeast and human cells indicate that recruitment of telomerase to a telomere may be influenced by multiple variables, including regulatory protein factors, hTERT domains, telomere length, and the cell cycle stage. First, in yeast, the telomerase associated factor Est1 and the single-strand DNA binding protein Cdc13 play roles in telomerase recruitment (Pennock et al. 2001; Bianchi et al. 2004). Analogous proteins exist in human cells (Est1A, Est1B, Est1C, and POT1, respectively); however, how or whether these proteins are directly involved in telomerase recruitment remains to be elucidated. Second, N-terminal residues of hTERT within the DAT (dissociate the activities of telomerase) domain may have a role in binding single stranded telomeric DNA as the "anchor site" (Lee et al. 1993; Moriarty et al. 2005). Third, a cis-acting mechanism in yeast and humans that regulates telomere length maintenance may modulate telomerase access to the telomere (reviewed in Blackburn 2001; Smogorzewska and de Lange, 2004). Long telomeres, which have more associated protein factors, are in a state that is acted on by telomerase less frequently than that of short telomeres, which have fewer associated factors. Whether short telomeres actively recruit telomerase remains to be determined. Last, the recruitment of telomerase to telomeres shows cell-cycle regulation (Taggart et al. 2002; Smith et al. 2003; Fisher et al. 2004; Jady et al. 2006; Tomlinson et al. 2006). Presence of the telomeric protection complex shelterin at telomeres is necessary for the recruitment of telomerase. ACD (TPP1), the subunit of the shelterin complex, directly interacts, through its TEL patch region, with telomerase and is required for telomerase function in vivo (Abreu et al. 2010, Nandakumar et al. 2012, Sexton et al. 2014). The interaction involves the TEN domain of TERT (Schmidt et al. 2014).
The helicase RTEL1 is recruited to telomeres in S phase via direct interaction with the shelterin complex subunit TREF2. RTEL1 is needed for T-loop unwinding and resolution of telomeric G-quadruplex (G4) DNA structures, necessary steps for efficient telomere replication (Vannier et al. 2012, Sarek et al. 2015). Germline mutations in RTEL1 cause a severe form of dyskeratosis congenita, a telomere disorder syndrome, called Hoyeraal Hreidarsson syndrome (Ballew, Yeager et al. 2013; Walne et al. 2013; Ballew, Joseph et al. 2013, Le Guen et al. 2013, Deng et al. 2013). Loading of RTEL1 to telomere ends is negatively regulated outside of S phase by CDK2:CCNA-mediated phosphorylation of the shelterin complex subunit TERF2 at serine residue S365. At the S phase entry, TERF2 is dephosphorylated by the PP6 phosphatase, thus allowing timely RTEL1 loading (Sarek et al. 2019).

Literature References
PubMed ID Title Journal Year
15060173 Rescue of an hTERT mutant defective in telomere elongation by fusion with hPot1

Armbruster, BN, Linardic, CM, Veldman, T, Bansal, NP, Downie, DL, Counter, CM

Mol Cell Biol 2004
25620558 TRF2 recruits RTEL1 to telomeres in S phase to promote t-loop unwinding

Sarek, G, Vannier, JB, Panier, S, Petrini, JHJ, Boulton, SJ

Mol. Cell 2015
22579284 RTEL1 dismantles T loops and counteracts telomeric G4-DNA to maintain telomere integrity

Vannier, JB, Pavicic-Kaltenbrunner, V, Petalcorin, MI, Ding, H, Boulton, SJ

Cell 2012
25128433 Genetic and molecular identification of three human TPP1 functions in telomerase action: recruitment, activation, and homeostasis set point regulation

Sexton, AN, Regalado, SG, Lai, CS, Cost, GJ, O'Neil, CM, Urnov, FD, Gregory, PD, Jaenisch, R, Collins, K, Hockemeyer, D

Genes Dev. 2014
20404094 TIN2-tethered TPP1 recruits human telomerase to telomeres in vivo

Abreu, E, Aritonovska, E, Reichenbach, P, Cristofari, G, Culp, B, Terns, RM, Lingner, J, Terns, MP

Mol. Cell. Biol. 2010
31723267 CDK phosphorylation of TRF2 controls t-loop dynamics during the cell cycle

Sarek, G, Kotsantis, P, Ruis, P, Van Ly, D, Margalef, P, Borel, V, Zheng, XF, Flynn, HR, Snijders, AP, Chowdhury, D, Cesare, AJ, Boulton, SJ

Nature 2019
23103865 The TEL patch of telomere protein TPP1 mediates telomerase recruitment and processivity

Nandakumar, J, Bell, CF, Weidenfeld, I, Zaug, AJ, Leinwand, LA, Cech, TR

Nature 2012
25271372 Identification of human TERT elements necessary for telomerase recruitment to telomeres

Schmidt, JC, Dalby, AB, Cech, TR

Elife 2014
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