Abstract
Chromosome ends are protected from erosion and chromosomal fusions through telomeric repeats and the telomere-binding protein complex shelterin. Imperfect repetitive sequences, known as telomere-associated sequences (TAS), flank the telomeres, yet their function is not well understood. In this perspective, we discuss our recent findings demonstrating that the TAS, in Schizosaccharomyces pombe, are organized into a distinct chromatin domain that is marked by low nucleosome levels and is highly recombinogenic (van Emden et al. in EMBO Rep 20:e47181. https://doi.org/10.15252/embr.201847181, 2019). Low nucleosome abundance at the TAS is independent of the chromosomal position, but is an intrinsic property of the DNA sequence itself. Critical nucleosome levels are maintained through two heterochromatin complexes recruited by the shelterin subunit Ccq1, which together control gene repression and nucleosome stability. Furthermore, Ccq1 inhibits TAS-facilitated recombination between subtelomeres, yet independently of nucleosome stability. In conclusion, the TAS present a unique chromatin environment causing nucleosome loss and genome instability, which are both counteracted by Ccq1 through independent mechanisms. Given the antagonistic behavior, we hypothesize that Ccq1 co-evolved with the appearance of TAS to regulate nucleosome dynamics and recombination-based telomere maintenance in the absence of telomerase.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Abreu E, Aritonovska E, Reichenbach P, Cristofari G, Culp B, Terns RM, Lingner J, Terns MP (2010) TIN2-tethered TPP1 recruits human telomerase to telomeres in vivo. Mol Cell Biol 30:2971–2982. https://doi.org/10.1128/MCB.00240-10
Ambrosini A, Paul S, Hu S, Riethman H (2007) Human subtelomeric duplicon structure and organization. Genome Biol 8:R151. https://doi.org/10.1186/gb-2007-8-7-r151
Apte MS, Cooper JP (2017) Life and cancer without telomerase: ALT and other strategies for making sure ends (don’t) meet. Crit Rev Biochem Mol Biol 52:57–73. https://doi.org/10.1080/10409238.2016.1260090
Armstrong CA, Moiseeva V, Collopy LC, Pearson SR, Ullah TR, Xi ST, Martin J, Subramaniam S, Marelli S, Amelina H, Tomita K (2018) Fission yeast Ccq1 is a modulator of telomerase activity. Nucleic Acids Res 46:704–716. https://doi.org/10.1093/nar/gkx1223
Baumann P, Cech TR (2000) Protection of telomeres by the Ku protein in fission yeast. Mol Biol Cell 11:3265–3275. https://doi.org/10.1091/mbc.11.10.3265
Baumann P, Cech TR (2001) Pot1, the putative telomere end-binding protein in fission yeast and humans. Science 292:1171–1175. https://doi.org/10.1126/science.1060036
Blasco MA (2007) The epigenetic regulation of mammalian telomeres. Nat Rev Genet 8:299–309. https://doi.org/10.1038/nrg2047
Chaudari A, Huberman JA (2012) Identification of two telomere-proximal fission yeast DNA replication origins constrained by nearby cis-acting sequences to replicate in late S phase. F1000Res 1:58. https://doi.org/10.12688/f1000research.1-58.v1
Chuang RY, Kelly TJ (1999) The fission yeast homologue of Orc4p binds to replication origin DNA via multiple AT-hooks. Proc Natl Acad Sci USA 96:2656–2661
Cooper JP, Nimmo ER, Allshire RC, Cech TR (1997) Regulation of telomere length and function by a Myb-domain protein in fission yeast. Nature 385:744–747. https://doi.org/10.1038/385744a0
Creamer KM, Job G, Shanker S, Neale GA, Lin Y-C, Bartholomew B, Partridge JF (2014) The Mi-2 homolog Mit1 actively positions nucleosomes within heterochromatin to suppress transcription. Mol Cell Biol 34:2046–2061. https://doi.org/10.1128/MCB.01609-13
de Lange T (2015) A loopy view of telomere evolution. Front Genet 6:321. https://doi.org/10.3389/fgene.2015.00321
De Vries BBA, Winter R, Schinzel A, van Ravenswaaij-Arts C (2003) Telomeres: a diagnosis at the end of the chromosomes. J Med Genet 40:385–398. https://doi.org/10.1136/jmg.40.6.385
Dehé P-M, Cooper JP (2010) Fission yeast telomeres forecast the end of the crisis. FEBS Lett 584:3725–3733. https://doi.org/10.1016/j.febslet.2010.07.045
Duraisingh MT, Horn D (2016) Epigenetic regulation of virulence gene expression in parasitic protozoa. Cell Host Microbe 19:629–640. https://doi.org/10.1016/j.chom.2016.04.020
Harland JL, Chang Y-T, Moser BA, Nakamura TM (2014) Tpz1-Ccq1 and Tpz1-Poz1 interactions within fission yeast shelterin modulate Ccq1 Thr93 phosphorylation and telomerase recruitment. PLoS Genet 10:e1004708. https://doi.org/10.1371/journal.pgen.1004708
Hong E-JE, Villén J, Gerace EL, Gygi SP, Moazed D (2005) A cullin E3 ubiquitin ligase complex associates with Rik1 and the Clr4 histone H3-K9 methyltransferase and is required for RNAi-mediated heterochromatin formation. RNA Biol 2:106–111
Horn PJ, Bastie J-N, Peterson CL (2005) A Rik1-associated, cullin-dependent E3 ubiquitin ligase is essential for heterochromatin formation. Genes Dev 19:1705–1714. https://doi.org/10.1101/gad.1328005
Jain D, Hebden AK, Nakamura TM, Miller KM, Cooper JP (2010) HAATI survivors replace canonical telomeres with blocks of generic heterochromatin. Nature 467:223–227. https://doi.org/10.1038/nature09374
Jia S, Kobayashi R, Grewal SIS (2005) Ubiquitin ligase component Cul4 associates with Clr4 histone methyltransferase to assemble heterochromatin. Nat Cell Biol 7:1007–1013. https://doi.org/10.1038/ncb1300
Job G, Brugger C, Xu T, Lowe BR, Pfister Y, Qu C, Shanker S, Baños Sanz JI, Partridge JF, Schalch T (2016) SHREC silences heterochromatin via distinct remodeling and deacetylation modules. Mol Cell 62:207–221. https://doi.org/10.1016/j.molcel.2016.03.016
Johnsson A, Durand-Dubief M, Xue-Franzén Y, Rönnerblad M, Ekwall K, Wright A (2009) HAT-HDAC interplay modulates global histone H3K14 acetylation in gene-coding regions during stress. EMBO Rep 10:1009–1014. https://doi.org/10.1038/embor.2009.127
Kanoh J, Sadaie M, Urano T, Ishikawa F (2005) Telomere binding protein Taz1 establishes Swi6 heterochromatin independently of RNAi at telomeres. Curr Biol 15:1808–1819. https://doi.org/10.1016/j.cub.2005.09.041
Khair L, Subramanian L, Moser BA, Nakamura TM (2010) Roles of heterochromatin and telomere proteins in regulation of fission yeast telomere recombination and telomerase recruitment. J Biol Chem 285:5327–5337. https://doi.org/10.1074/jbc.M109.078840
Li F, Goto DB, Zaratiegui M, Tang X, Martienssen R, Cande WZ (2005) Two novel proteins, dos1 and dos2, interact with rik1 to regulate heterochromatic RNA interference and histone modification. Curr Biol 15:1448–1457. https://doi.org/10.1016/j.cub.2005.07.021
Maestroni L, Géli V, Coulon S (2018) STEEx, a boundary between the world of quiescence and the vegetative cycle. Curr Genet 64:901–905. https://doi.org/10.1007/s00294-018-0808-x
Mason JMO, McEachern MJ (2018) Chromosome ends as adaptive beginnings: the potential role of dysfunctional telomeres in subtelomeric evolvability. Curr Genet 64:997–1000. https://doi.org/10.1007/s00294-018-0822-z
McEachern MJ, Haber JE (2006) Break-induced replication and recombinational telomere elongation in yeast. Annu Rev Biochem 75:111–135. https://doi.org/10.1146/annurev.biochem.74.082803.133234
Miyoshi T, Kanoh J, Saito M, Ishikawa F (2008) Fission yeast Pot1-Tpp1 protects telomeres and regulates telomere length. Science 320:1341–1344. https://doi.org/10.1126/science.1154819
Moravec M, Wischnewski H, Bah A, Hu Y, Liu N, Lafranchi L, King MC, Azzalin CM (2016) TERRA promotes telomerase-mediated telomere elongation in Schizosaccharomyces pombe. EMBO Rep 17:999–1012. https://doi.org/10.15252/embr.201541708
Moser BA, Raguimova ON, Nakamura TM (2015) Ccq1-Tpz1TPP1 interaction facilitates telomerase and SHREC association with telomeres in fission yeast. Mol Biol Cell 26:3857–3866. https://doi.org/10.1091/mbc.E15-07-0481
Nakamura TM, Morin GB, Chapman KB, Weinrich SL, Andrews WH, Lingner J, Harley CB, Cech TR (1997) Telomerase catalytic subunit homologs from fission yeast and human. Science 277:955–959
Nakamura TM, Cooper JP, Cech TR (1998) Two modes of survival of fission yeast without telomerase. Science 282:493–496
Palm W, de Lange T (2008) How shelterin protects mammalian telomeres. Annu Rev Genet 42:301–334. https://doi.org/10.1146/annurev.genet.41.110306.130350
Riethman H, Ambrosini A, Paul S (2005) Human subtelomere structure and variation. Chromosome Res 13:505–515. https://doi.org/10.1007/s10577-005-0998-1
Sugawara NF (1988) DNA sequences at the telomeres of the fission yeast S. pombe. thesis. Harvard University, Cambridge
Sugiyama T, Cam HP, Sugiyama R, Noma K-I, Zofall M, Kobayashi R, Grewal SIS (2007) SHREC, an effector complex for heterochromatic transcriptional silencing. Cell 128:491–504. https://doi.org/10.1016/j.cell.2006.12.035
Takai KK, Kibe T, Donigian JR, Frescas D, de Lange T (2011) Telomere protection by TPP1/POT1 requires tethering to TIN2. Mol Cell 44:647–659. https://doi.org/10.1016/j.molcel.2011.08.043
Tashiro S, Nishihara Y, Kugou K, Ohta K, Kanoh J (2017) Subtelomeres constitute a safeguard for gene expression and chromosome homeostasis. Nucleic Acids Res 45:10333–10349. https://doi.org/10.1093/nar/gkx780
Thon G, Hansen KR, Altes SP, Sidhu D, Singh G, Verhein-Hansen J, Bonaduce MJ, Klar AJS (2005) The Clr7 and Clr8 directionality factors and the Pcu4 cullin mediate heterochromatin formation in the fission yeast Schizosaccharomyces pombe. Genetics 171:1583–1595. https://doi.org/10.1534/genetics.105.048298
Tomita K (2018) How long does telomerase extend telomeres? Regulation of telomerase release and telomere length homeostasis. Curr Genet 64:1177–1181. https://doi.org/10.1007/s00294-018-0836-6
Tomita K, Cooper JP (2008) Fission yeast Ccq1 is telomerase recruiter and local checkpoint controller. Genes Dev 22:3461–3474. https://doi.org/10.1101/gad.498608
van Emden TS, Forn M, Forné I, Sarkadi Z, Capella M, Martín Caballero L, Fischer-Burkart S, Brönner C, Simonetta M, Toczyski D, Halic M, Imhof A, Braun S (2019) Shelterin and subtelomeric DNA sequences control nucleosome maintenance and genome stability. EMBO Rep 20:e47181. https://doi.org/10.15252/embr.201847181
Wang J, Cohen AL, Letian A, Tadeo X, Moresco JJ, Liu J, Yates JR, Qiao F, Jia S (2016) The proper connection between shelterin components is required for telomeric heterochromatin assembly. Genes Dev 30:827–839. https://doi.org/10.1101/gad.266718.115
Wood V, Gwilliam R, Rajandream M-A, Lyne M, Lyne R, Stewart A, Sgouros J, Peat N, Hayles J, Baker S, Basham D, Bowman S, Brooks K, Brown D, Brown S, Chillingworth T, Churcher C, Collins M, Connor R, Cronin A, Davis P, Feltwell T, Fraser A, Gentles S, Goble A, Hamlin N, Harris D, Hidalgo J, Hodgson G, Holroyd S, Hornsby T, Howarth S, Huckle EJ, Hunt S, Jagels K, James K, Jones L, Jones M, Leather S, McDonald S, McLean J, Mooney P, Moule S, Mungall K, Murphy L, Niblett D, Odell C, Oliver K, O’Neil S, Pearson D, Quail MA, Rabbinowitsch E, Rutherford K, Rutter S, Saunders D, Seeger K, Sharp S, Skelton J, Simmonds M, Squares R, Squares S, Stevens K, Taylor K, Taylor RG, Tivey A, Walsh S, Warren T, Whitehead S, Woodward J, Volckaert G, Aert R, Robben J, Grymonprez B, Weltjens I, Vanstreels E, Rieger M, Schäfer M, Müller-Auer S, Gabel C, Fuchs M, Düsterhöft A, Fritzc C, Holzer E, Moestl D, Hilbert H, Borzym K, Langer I, Beck A, Lehrach H, Reinhardt R, Pohl TM, Eger P, Zimmermann W, Wedler H, Wambutt R, Purnelle B, Goffeau A, Cadieu E, Dréano S, Gloux S, Lelaure V, Mottier S, Galibert F, Aves SJ, Xiang Z, Hunt C, Moore K, Hurst SM, Lucas M, Rochet M, Gaillardin C, Tallada VA, Garzon A, Thode G, Daga RR, Cruzado L, Jimenez J, Sánchez M, del Rey F, Benito J, Domínguez A, Revuelta JL, Moreno S, Armstrong J, Forsburg SL, Cerutti L, Lowe T, McCombie WR, Paulsen I, Potashkin J, Shpakovski GV, Ussery D, Barrell BG, Nurse P, Cerrutti L (2002) The genome sequence of Schizosaccharomyces pombe. Nature 415:871–880. https://doi.org/10.1038/nature724
Workman JL (2006) Nucleosome displacement in transcription. Genes Dev 20:2009–2017. https://doi.org/10.1101/gad.1435706
Xi L, Fondufe-Mittendorf Y, Xia L, Flatow J, Widom J, Wang J-P (2010) Predicting nucleosome positioning using a duration Hidden Markov Model. BMC Bioinformatics 11:346. https://doi.org/10.1186/1471-2105-11-346
Xin H, Liu D, Wan M, Safari A, Kim H, Sun W, O’Connor MS, Songyang Z (2007) TPP1 is a homologue of ciliate TEBP-beta and interacts with POT1 to recruit telomerase. Nature 445:559–562. https://doi.org/10.1038/nature05469
Zhong Z, Shiue L, Kaplan S, de Lange T (1992) A mammalian factor that binds telomeric TTAGGG repeats in vitro. Mol Cell Biol 12:4834–4843
Zofall M, Smith DR, Mizuguchi T, Dhakshnamoorthy J, Grewal SIS (2016) Taz1-Shelterin promotes facultative heterochromatin assembly at chromosome-internal sites containing late replication origins. Mol Cell 62:862–874. https://doi.org/10.1016/j.molcel.2016.04.034
Acknowledgements
We thank the members of the Braun Lab for critical reading of this manuscript. This work was supported by grants awarded to S.B. from the German Research Foundation (BR 3511/2-1; SFB 1064-A25) and the European Union Network of Excellence EpiGeneSys (HEALTH-2010-257082).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Additional information
Communicated by M. Kupiec.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
van Emden, T.S., Braun, S. TASks for subtelomeres: when nucleosome loss and genome instability are favored. Curr Genet 65, 1153–1160 (2019). https://doi.org/10.1007/s00294-019-00986-8
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00294-019-00986-8