A Protein-Counting Mechanism for Telomere Length Regulation in Yeast
Open accessAbstract
In the yeast Saccharomyces cerevisiae , telomere elongation is negatively regulated by the telomere repeat-binding protein Rap1p, such that a narrow length distribution of telomere repeat tracts is observed. This length regulation was shown to function independently of the orientation of the telomere repeats. The number of repeats at an individual telomere was reduced when hybrid proteins containing the Rap1p carboxyl terminus were targeted there by a heterologous DNA-binding domain. The extent of this telomere tract shortening was proportional to the number of targeted molecules, consistent with a feedback mechanism of telomere length regulation that can discriminate the precise number of Rap1p molecules bound to the chromosome end.
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A strong common theme that has emerged is the likely involvement of a protein-counting mechanism in both yeast and mammals.
“However, a strong common theme that has emerged is the likely involvement of a protein-counting mechanism in both systems (31, 44).”
From Control of Human Telomere Length by TRF1 and TRF2 (2000) · cites this paper as [31]
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“There is currently a general consensus that telomerase is preferentially recruited to the shortest telomeres (Bianchi and Shore, 2008; Hemann et al., 2001; Marcand et al., 1997; Ouellette et al., 2000; Samper et al., 2001; Zhu et al., 1998).”
BackgroundScholes, D. T., Banerjee, M., Bowen, B., & Curcio, M. J. (2001) · Genetics · doi:10.1093/genetics/159.4.1449 · Cited by 235 · see citing works
Structure and Function in the Budding Yeast Nucleus
Taddei, A., & Gasser, S. M. (2012) · Genetics · doi:10.1534/genetics.112.140608 · Cited by 225 · see citing works
A RAP1/TRF2 Complex Inhibits Nonhomologous End-Joining at Human Telomeric DNA Ends
Bae, N. S., & Baumann, P. (2007) · Molecular Cell · doi:10.1016/j.molcel.2007.03.023 · Cited by 215 · see citing works
“Instead, RAP1 binds directly to telomeric sequences (Conrad et al., 1990; Konig et al., 1996) where it functions in telomere length regulation (Marcand et al., 1997) and prevents telomere fusions by NHEJ (Pardo and Marcand, 2005).”
TRF1 binds a bipartite telomeric site with extreme spatial flexibility
Bianchi, A., Stansel, R. M., Fairall, L., Griffith, J. D., Rhodes, D., & de Lange, T. (1999) · The EMBO Journal · doi:10.1093/emboj/18.20.5735 · Cited by 217 · see citing works
“The Myb-type DNA binding domain is a helix–turn– helix (HTH) motif usually present in multiple tandem copies in the large class of Myb-related proteins that function as transcriptional regulators of cell growth and differentiation (for review see Lipsick, 1996; Martin and Paz-Ares, 1997).”
BackgroundProgressive cis‐inhibition of telomerase upon telomere elongation
Marcand, S., Brevet, V., & Gilson, É. (1999) · The EMBO Journal · doi:10.1093/emboj/18.12.3509 · Cited by 213 · see citing works
“This negative feedback appears to be mediated by a protein-counting mechanism that can discriminate the precise number of Rap1p molecules bound to a telomere (Kyrion et al., 1992; Brun et al., 1997; Marcand et al., 1997; Ray and Runge, 1999).”
BackgroundMethodInfluentialSelf-citationA ‘higher order’ of telomere regulation: telomere heterochromatin and telomeric RNAs
Schoeftner, S., & Blasco, M. A. (2009) · The EMBO Journal · doi:10.1038/emboj.2009.197 · Cited by 214 · see citing works
“In addition, the Rap1 counting pathway seems to be indirectly regulated by the Sir proteins (Marcand et al, 1997).”
BackgroundHuman Protection of Telomeres 1 (POT1) Is a Negative Regulator of Telomerase Activity In Vitro
Kelleher, C. D., Kurth, I., & Lingner, J. (2005) · Molecular and Cellular Biology · doi:10.1128/mcb.25.2.808-818.2005 · Cited by 211 · see citing works
“In budding yeast, the duplex telomere binding protein Rap1p has been implicated in telomere length regulation, controlling telomerase activity at individual telomere ends as a function of the number of Rap1 molecules bound (28, 31).”
BackgroundSilverman, J. S., Takai, H., Buonomo, S. B. C., Eisenhaber, F., & de Lange, T. (2004) · Genes & Development · doi:10.1101/gad.1216004 · Cited by 205 · see citing works
“Telomere-bound Rap1 recruits Rif1 and Rif2, which both limit extension of the telomeric tract by telomerase (Hardy et al. 1992; Marcand et al. 1997; Wotton and Shore 1997).”
BackgroundAncelin, K., Brunori, M., Bauwens, S., Koering, C.-E., Brun, C., Ricoul, M., Pommier, J., Sabatier, L., & Gilson, É. (2002) · Molecular and Cellular Biology · doi:10.1128/mcb.22.10.3474-3487.2002 · Cited by 204 · see citing works
“It was previously reported that in yeast, mammalian cells, and Trypanosoma, an inverse relation between telomere elongation and telomere length exists, providing a negative-feedback loop that maintains telomeres at a defined mean length (19, 33, 49, 51, 61, 70).”
BackgroundA two-step model for senescence triggered by a single critically short telomere
Abdallah, P., Luciano, P., Runge, K. W., Lisby, M., Géli, V., Gilson, E., & Teixeira, M. T. (2009) · Nature Cell Biology · doi:10.1038/ncb1911 · Cited by 190 · see citing works
Telomeric Strategies: Means to an End
Jain, D., & Cooper, J. P. (2010) · Annual Review of Genetics · doi:10.1146/annurev-genet-102108-134841 · Cited by 196 · see citing works
“Elegant budding yeast experiments in which Rap1 was artificially tethered to telomeres showed that Rap1 inhibits telomerase action in a manner proportional to the number of tethered Rap1 molecules (123).”
BackgroundEngelhardt, M. M., Drullinsky, P. R., Guillem, J. G., & Moore, M. A. S. (1997) · PubMed · Cited by 189 · see citing works
Chromosome ends: all the same under their caps
Pryde, F. E., Gorham, H. C., & Louis, E. J. (1997) · Current Opinion in Genetics & Development · doi:10.1016/s0959-437x(97)80046-9 · Cited by 187 · see citing works
Bártková, J., Thullberg, M., Meyts, E. R., Skakkebæk, N. E., & Bartek, J. (2000) · International Journal of Cancer · doi:10.1002/(sici)1097-0215(20000201)85:3 · Cited by 70 · see citing works
The Individual Blood Cell Telomere Attrition Rate Is Telomere Length Dependent
Nordfjäll, K., Svenson, U., Norrback, K., Adolfsson, R., Lenner, P., & Roos, G. (2009) · PLoS Genetics · doi:10.1371/journal.pgen.1000375 · Cited by 184 · see citing works
“seem to have a telomere maintenance system that gives priority to short telomeres. Based on human cross-sectional studies of age-associated telomere attrition, it has been speculated that TL at a certain age can predict a theoretical future life span. Our findings indicate that TL regulation through life might be more…”
BackgroundInTERTpreting telomerase structure and function
Wyatt, H. D. M., West, S. C., & Beattie, T. L. (2010) · Nucleic Acids Research · doi:10.1093/nar/gkq370 · Cited by 183 · see citing works
Rap1 prevents telomere fusions by nonhomologous end joining
Pardo, B., & Marcand, S. (2005) · The EMBO Journal · doi:10.1038/sj.emboj.7600778 · Cited by 179 · see citing works
“Indeed, another function of Rap1 at telomeres is to negatively regulate telomere elongation by telomerase (Kyrion et al, 1992; Marcand et al, 1997).”
BackgroundSelf-citationDNA damage response at functional and dysfunctional telomeresPreprint
Longhese, M. P. (2008) · Genes & Development · doi:10.1101/gad.1626908 · Cited by 180 · see citing works
“A critical feature of this in cis negative regulation of telomerase access is the ability of shelterin to limit telomere length based on its total telomere-bound amount, which generates an inhibitory effect on telomerase, whose strength increases with increasing TG tract length (Marcand et al. 1997).”
BackgroundSadowsky, J., Fairlie, W. D., Hadley, E. B., Lee, H., Umezawa, N., Nikolovska‐Coleska, Z., Wang, S., Huang, D. C. S., Tomita, Y. A., & Gellman, S. H. (2006) · Journal of the American Chemical Society · doi:10.1021/ja0662523 · Cited by 175 · see citing works
Saretzki, G. C., Sitte, N., Merkel, U., Wurm, R. E., & von Zglinicki, T. (1999) · Oncogene · doi:10.1038/sj.onc.1202898 · Cited by 171 · see citing works
“This result is in contrast to the situation in yeast (Krauskopf and Blackburn, 1996; Marcand et al., 1997), but in accordance with data showing a p53-dependent telomere length regulation in lung cancer cells (Mukhopadhyay et al., 1998).”
ResultSadowsky, J., Schmitt, M. A., Lee, H., Umezawa, N., Wang, S., Tomita, Y. A., & Gellman, S. H. (2005) · Journal of the American Chemical Society · doi:10.1021/ja053678t · Cited by 173 · see citing works
Rap1 Affects the Length and Heterogeneity of Human Telomeres
Li, B., & de Lange, T. (2003) · Molecular Biology of the Cell · doi:10.1091/mbc.e03-06-0403 · Cited by 172 · see citing works
“…rearrangements within the telomeric complex, Rap1 acts as a negative regulator of telomere length in both fission yeast and two budding yeasts (Conrad et al., 1990; Lustig et al., 1990; Krauskopf and Blackburn, 1996; Marcand et al., 1997a,b; Chikashige and Hiraoka, 2001; Kanoh and Ishikawa , 2001).”
InfluentialFrank-Vaillant, M., & Marcand, S. (2001) · Genes & Development · doi:10.1101/gad.206801 · Cited by 166 · see citing works
“Strain Lev360 results from the transformation of JKM179 with the linearized plasmid sp59 (Marcand et al. 1997).”
BackgroundMethodInfluentialSelf-citationRole of shelterin in cancer and aging
Martínez, P., & Blasco, M. A. (2010) · Aging Cell · doi:10.1111/j.1474-9726.2010.00596.x · Cited by 162 · see citing works
“controls telomere length and the establishment of subtelomeric silencing through recruitment of the Sir proteins (Kyrion et al., 1993; Hecht et al., 1995; Marcand et al., 1997; Tanny et al., 1999; Imai et al., 2000; Carmen et al., 2002).”
BackgroundHow Telomerase Reaches Its End: Mechanism of Telomerase Regulation by the Telomeric Complex
Bianchi, A., & Shore, D. (2008) · Molecular Cell · doi:10.1016/j.molcel.2008.06.013 · Cited by 157 · see citing works
“…telomere through a heterologous DNA-binding domain suggested that Rap1 molecules are ‘‘counted’’ by the machinery that leads to telomerase (in)activation and, thus, provided a conceptual framework for how telomerase might be selectively repressed in cis at longer telomeres (Marcand et al., 1997).”
BackgroundSelf-citationTERRA biogenesis, turnover and implications for function
Feuerhahn, S., Iglesias, N., Panza, A., Porro, A., & Lingner, J. (2010) · FEBS Letters · doi:10.1016/j.febslet.2010.07.032 · Cited by 151 · see citing works
“Budding yeast Rap1 binds directly double-stranded telomeric DNA and it plays a major role in telomere length regulation [21], chromosome end protection [22] and silencing of genes near telomeres, a phenomenon known as telomere position effect (TPE) [23].”
BackgroundRevisiting Telomere Shortening in Cancer
Okamoto, K., & Seimiya, H. (2019) · Cells · doi:10.3390/cells8020107 · Cited by 153 · see citing works
“As a well-established mechanism for limited telomere elongation, telomere-bound shelterin complexes exert a negative feedback effect on telomerase access to telomeres (so-called “protein-counting” mechanism) [115,116].”
BackgroundDevelopmental Control of Telomere Lengths and Telomerase Activity in Plants
Říha, K., Fajkus, J., Široký, J., & Vyskot, B. (1998) · The Plant Cell · doi:10.1105/tpc.10.10.1691 · Cited by 152 · see citing works
“A protein-counting mechanism for telomere length regulation was described for yeast in which the Rap1p telomere binding protein plays a key role (Marcand et al., 1997).”
Pol12, the B subunit of DNA polymerase α, functions in both telomere capping and length regulationPreprint
Grossi, S., Puglisi, A., Dmitriev, P., Lopes, M., & Shore, D. (2004) · Genes & Development · doi:10.1101/gad.300004 · Cited by 151 · see citing works
“Maintenance of telomere length about a fixed average value is achieved through a mechanism that appears to measure not the TG-repeat tract length per se, but, rather, the number of Rap1 proteins bound to it (Marcand et al. 1997; Ray and Runge 1999a).”
BackgroundMethodSelf-citationCellular senescence in musculoskeletal homeostasis, diseases, and regeneration
Wan, M., Gray-Gaillard, E. F., & Elisseeff, J. H. (2021) · Bone Research · doi:10.1038/s41413-021-00164-y · Cited by 150 · see citing works
TRF1 promotes parallel pairing of telomeric tracts in vitro
Griffith, J., Bianchi, A., & de Lange, T. (1998) · Journal of Molecular Biology · doi:10.1006/jmbi.1998.1686 · Cited by 148 · see citing works
“Recent data favor a protein-counting model for the telomere length homeostasis by Rap1p (Marcand et al., 1997).”
InfluentialMishra, K., & Shore, D. (1999) · Current Biology · doi:10.1016/s0960-9822(99)80483-7 · Cited by 147 · see citing works
Self-citationEsc1, a Nuclear Periphery Protein Required for Sir4-Based Plasmid Anchoring and Partitioning
Andrulis, E. D., Zappulla, D. C., Ansari, A., Perrod, S., Laiosa, C. V., Gartenberg, M. R., & Sternglanz, R. (2002) · Molecular and Cellular Biology · doi:10.1128/mcb.22.23.8292-8301.2002 · Cited by 147 · see citing works
“Lev8 was transformed with a GBD hybrid plasmid library and screened for GBD fusion on M ay 1, 2019 by guest http://m cb.asm .org/ D ow nloaded from proteins that restored silencing of the telomeric URA3.”
BackgroundMethodInfluentialHuman telomeric proteins occupy selective interstitial sites
Yang, D., Xiong, Y., Kim, H., He, Q., Li, Y., Chen, R., & Songyang, Z. (2011) · Cell Research · doi:10.1038/cr.2011.39 · Cited by 141 · see citing works
Mammalian Rif1 contributes to replication stress survival and homology-directed repair
Buonomo, S. B. C., Wu, Y., Ferguson, D. O., & de Lange, T. (2009) · The Journal of Cell Biology · doi:10.1083/jcb.200902039 · Cited by 141 · see citing works
“S phase checkpoint, contributing to the inhibition of DNA replication associated with the activation of ATM (Silverman et al., 2004).”
Replication of Telomeres and the Regulation of TelomerasePreprint
Pfeiffer, V., & Lingner, J. (2013) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a010405 · Cited by 137 · see citing works
“The frequency of elongation is regulated by the numberof Rap1/Rif1/Rif2 proteins that are bound to telomeres in dependence of their length (Marcand et al. 1997).”
BackgroundTelomere length regulation: coupling DNA end processing to feedback regulation of telomerase
Shore, D., & Bianchi, A. (2009) · The EMBO Journal · doi:10.1038/emboj.2009.195 · Cited by 138 · see citing works
“In the course of studying the effect of Rap1 on telomeric gene silencing, Marcand et al (1997) noticed that tethering of hybrid proteins containing the Rap1 C-terminus adjacent to a single-telomeric TG tract would reduce the length of that telomere, in a manner roughly proportional to the number of…”
BackgroundInfluentialSelf-citationPositive and negative regulation of telomerase access to the telomere
Evans, S. K., & Lundblad, V. (2000) · Journal of Cell Science · doi:10.1242/jcs.113.19.3357 · Cited by 135 · see citing works
Yin, H. H., Lee, G.-I., Sedey, K. A., Rodriguez, J. M., Wang, H., Sebti, S. M., & Hamilton, A. D. (2005) · Journal of the American Chemical Society · doi:10.1021/ja0446404 · Cited by 138 · see citing works
Wendt, M. D., Wang, S., Kunzer, A. R., McClellan, W. J., Bruncko, M., Oost, T. K., Ding, H., Joseph, M. K., Zhang, H., Nimmer, P. M., et al. (2006) · Journal of Medicinal Chemistry · doi:10.1021/jm050754u · Cited by 137 · see citing works
Increased association of telomerase with short telomeres in yeastPreprint
Bianchi, A., & Shore, D. (2007) · Genes & Development · doi:10.1101/gad.438907 · Cited by 130 · see citing works
“A critical feature of the negative regulation of telomerase in cis at chromosome ends is the apparent ability of the telomeric complex to gauge telomere length based on the number of telomere repeatbound regulators (Rap1 and Rif proteins in yeast) (Marcand et al. 1997; Levy and Blackburn 2004).”
Self-citation
- Authors
- Marcand, S., Gilson, E., & Shore, D.
- Affiliations
- École Normale Supérieure de Lyon (FR)
- E. Gilson, Laboratoire de Biologie Moléculaire et Cellulaire, Ecole Normale Supérieure de Lyon, UMR49 CNRS/ENSL, 69364 Lyon Cédex 07, France.
- University of Geneva (CH)
- Corresponding author
- Marcand, Stéphane
- Shore, David
- Venue
- Science
- Published
- 1997-02-14
- Volume
- 275
- Issue
- 5302
- Pages
- 986-990
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- OpenAlex
- W1978002329
- Cited by
- 524
- References
- 38
- Citations by year
- 2026: 10 · 2025: 4 · 2024: 7 · 2023: 6 · 2022: 5 · 2021: 14 · 2020: 5 · 2019: 17 · 2018: 10 · 2017: 12 · 2016: 13 · 2015: 9 · 2014: 14 · 2013: 14 · 2012: 10
- FWCI
- 23.60
- Type
- journal article
- Language
- en
- Open access
- Licence
- cc-by
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- Archive ouverte UNIGE (University of Geneva) (submittedVersion, cc-by)
- Funders
- National Institutes of Health (5r01gm040094-09)
- National Institute of General Medical Sciences (GM 40094)
- Topics
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- telomere length regulation, Rap1p, feedback regulation, protein-DNA interactions, telomere elongation, Saccharomyces cerevisiae, telomere shortening
- MeSH terms
- Binding Sites, Fungal Proteins, Genetic Markers, Mutation, Saccharomyces cerevisiae, Transformation, Genetic, Chromosomes, Fungal, Gene Expression Regulation, Fungal, Telomere, Telomerase, GTP-Binding Proteins, rap GTP-Binding Proteins
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