Telomeres avoid end detection by severing the checkpoint signal transduction pathway
Open accessAbstract
Telomeres protect the normal ends of chromosomes from being recognized as deleterious DNA double-strand breaks. Recent studies have uncovered an apparent paradox: although DNA repair is prevented, several proteins involved in DNA damage processing and checkpoint responses are recruited to telomeres in every cell cycle and are required for end protection. It is currently not understood how telomeres prevent DNA damage responses from causing permanent cell cycle arrest. Here we show that fission yeast (Schizosaccharomyces pombe) cells lacking Taz1, an orthologue of human TRF1 and TRF2 (ref. 2), recruit DNA repair proteins (Rad22(RAD52) and Rhp51(RAD51), where the superscript indicates the human orthologue) and checkpoint sensors (RPA, Rad9, Rad26(ATRIP) and Cut5/Rad4(TOPBP1)) to telomeres. Despite this, telomeres fail to accumulate the checkpoint mediator Crb2(53BP1) and, consequently, do not activate Chk1-dependent cell cycle arrest. Artificially recruiting Crb2(53BP1) to taz1Δ telomeres results in a full checkpoint response and cell cycle arrest. Stable association of Crb2(53BP1) to DNA double-strand breaks requires two independent histone modifications: H4 dimethylation at lysine 20 (H4K20me2) and H2A carboxy-terminal phosphorylation (γH2A). Whereas γH2A can be readily detected, telomeres lack H4K20me2, in contrast to internal chromosome locations. Blocking checkpoint signal transduction at telomeres requires Pot1 and Ccq1, and loss of either Pot1 or Ccq1 from telomeres leads to Crb2(53BP1) foci formation, Chk1 activation and cell cycle arrest. Thus, telomeres constitute a chromatin-privileged region of the chromosomes that lack essential epigenetic markers for DNA damage response amplification and cell cycle arrest. Because the protein kinases ATM and ATR must associate with telomeres in each S phase to recruit telomerase, exclusion of Crb2(53BP1) has a critical role in preventing telomeres from triggering cell cycle arrest.
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Dysfunctional telomeres trigger a DNA damage response but block attempted DNA repair.
“Dysfunctional telomeres elicit a DNA damage response (DDR) but suppress attempted DNA repair (22–25).”
From Aging, Cellular Senescence, and Cancer (2013) · cites this paper as [25]
The paper reports that dysfunctional taz1Δ telomeres undergo a DNA damage response, supporting the first half of the claim. But it says DNA repair proteins accumulate at those chromosome ends and concludes, “Thus, DNA repair is ongoing at taz1Δ chromosome ends” (Abstract; page not supplied). It describes suppression of checkpoint signaling and cell-cycle arrest, not suppression of repair at these dysfunctional telomeres. (LLM, conf=0.90)
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Cites
Longtine, M. S., Mckenzie, A., DeMarini, D. J., Shah, N. G., Wach, A., Brachat, A., Philippsen, P., & Pringle, J. R. (1998) · Yeast · doi:10.1002/(sici)1097-0061(199807)14:10 · Cited by 5,367 · see citing works
[56] Molecular genetic analysis of fission yeast Schizosaccharomyces pombe
Moreno, S., Klar, A., & Nurse, P. (1991) · Methods in Enzymology · doi:10.1016/0076-6879(91)94059-l · Cited by 3,620 · see citing works
Botuyan, M. V., Lee, J., Ward, I. M., Kim, J., Thompson, J. R., Chen, J., & Mer, G. (2006) · Cell · doi:10.1016/j.cell.2006.10.043 · Cited by 973 · see citing works
Protection of telomeres through independent control of ATM and ATR by TRF2 and POT1
Denchi, E. L., & de Lange, T. (2007) · Nature · doi:10.1038/nature06065 · Cited by 880 · see citing works
How Telomeres Solve the End-Protection Problem
de Lange, T. (2009) · Science · doi:10.1126/science.1170633 · Cited by 826 · see citing works
Li, B., Oestreich, S. C., & de Lange, T. (2000) · Cell · doi:10.1016/s0092-8674(00)80858-2 · Cited by 578 · see citing works
Methylation of Histone H4 Lysine 20 Controls Recruitment of Crb2 to Sites of DNA Damage
Sanders, S. L., Portoso, M., Mata, J., Bähler, J., Allshire, R. C., & Kouzarides, T. (2004) · Cell · doi:10.1016/j.cell.2004.11.009 · Cited by 545 · see citing works
Verdún, R. E., & Karlseder, J. (2006) · Cell · doi:10.1016/j.cell.2006.09.034 · Cited by 326 · see citing works
Functional Human Telomeres Are Recognized as DNA Damage in G2 of the Cell Cycle
Verdun, R. E., Crabbe, L., Haggblom, C., & Karlseder, J. (2005) · Molecular Cell · doi:10.1016/j.molcel.2005.09.024 · Cited by 284 · see citing works
Semi-conservative DNA replication through telomeres requires Taz1
Miller, K. M., Rog, O., & Cooper, J. P. (2006) · Nature · doi:10.1038/nature04638 · Cited by 268 · see citing works
Dysfunctional telomeres activate an ATM‐ATR‐dependent DNA damage response to suppress tumorigenesis
Guo, X., Deng, Y., Lin, Y., Cosme‐Blanco, W., Chan, S., He, H., Yuan, G., Brown, E. J., & Chang, S. (2007) · The EMBO Journal · doi:10.1038/sj.emboj.7601893 · Cited by 258 · see citing works
Fission Yeast Pot1-Tpp1 Protects Telomeres and Regulates Telomere Length
Miyoshi, T., Kanoh, J., Saito, M., & Ishikawa, F. (2008) · Science · doi:10.1126/science.1154819 · Cited by 227 · see citing works
Nakamura, T., Du, L., Redon, C. E., & Russell, P. R. (2004) · Molecular and Cellular Biology · doi:10.1128/mcb.24.14.6215-6230.2004 · Cited by 194 · see citing works
Self-citationA 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
Telomere binding of the Rap1 protein is required for meiosis in fission yeast
Chikashige, Y., & Hiraoka, Y. (2001) · Current Biology · doi:10.1016/s0960-9822(01)00457-2 · Cited by 175 · see citing works
The Fission Yeast Taz1 Protein Protects Chromosomes from Ku-Dependent End-to-End Fusions
Ferreira, M. G., & Cooper, J. P. (2001) · Molecular Cell · doi:10.1016/s1097-2765(01)00154-x · Cited by 173 · see citing works
Self-citationFerreira, M. G., & Cooper, J. P. (2004) · Genes & Development · doi:10.1101/gad.315804 · Cited by 152 · see citing works
Self-citationDu, L.-L., Nakamura, T., & Russell, P. R. (2006) · Genes & Development · doi:10.1101/gad.1422606 · Cited by 141 · see citing works
Self-citationTaz1, Rap1 and Rif1 act both interdependently and independently to maintain telomeres
Miller, K. M., Ferreira, M. G., & Cooper, J. P. (2005) · The EMBO Journal · doi:10.1038/sj.emboj.7600779 · Cited by 131 · see citing works
Self-citationGoudsouzian, L. K., Tuzon, C. T., & Zakian, V. A. (2006) · Molecular Cell · doi:10.1016/j.molcel.2006.10.005 · Cited by 114 · see citing works
Negrini, S., Ribaud, V., Bianchi, A., & Shore, D. (2007) · Genes & Development · doi:10.1101/gad.400907 · Cited by 93 · see citing works
Fission yeast Ccq1 is telomerase recruiter and local checkpoint controllerPreprint
Tomita, K., & Cooper, J. P. (2008) · Genes & Development · doi:10.1101/gad.498608 · Cited by 91 · see citing works
Differential arrival of leading and lagging strand DNA polymerases at fission yeast telomeres
Moser, B. A., Subramanian, L., Chang, Y.-T., Noguchi, C., Noguchi, E., & Nakamura, T. (2009) · The EMBO Journal · doi:10.1038/emboj.2009.31 · Cited by 74 · see citing works
Self-citationA telomeric repeat sequence adjacent to a DNA double-stranded break produces an anticheckpointPreprint
Michelson, R. J., Rosenstein, S., & Weinert, T. A. (2005) · Genes & Development · doi:10.1101/gad.1293805 · Cited by 73 · see citing works
Fission Yeast Dna2 Is Required for Generation of the Telomeric Single-Strand Overhang
Tomita, K., Kibe, T., Kang, H.-Y., Seo, Y., Uritani, M., Ushimaru, T., & Ueno, M. (2004) · Molecular and Cellular Biology · doi:10.1128/mcb.24.21.9557-9567.2004 · Cited by 72 · see citing works
Fission Yeast Tel1ATM and Rad3ATR Promote Telomere Protection and Telomerase Recruitment
Moser, B. A., Subramanian, L., Khair, L., et al. (2009) · PLoS Genetics · doi:10.1371/journal.pgen.1000622 · Cited by 70 · see citing works
Self-citationPot1 and cell cycle progression cooperate in telomere length regulation
Churikov, D., & Price, C. M. (2008) · Nature Structural & Molecular Biology · doi:10.1038/nsmb1331 · Cited by 67 · see citing works
Sumoylation of RecQ Helicase Controls the Fate of Dysfunctional Telomeres
Rog, O., Miller, K. M., Ferreira, M. G., & Cooper, J. P. (2009) · Molecular Cell · doi:10.1016/j.molcel.2009.01.027 · Cited by 66 · see citing works
Self-citationDi-methyl H4 Lysine 20 Targets the Checkpoint Protein Crb2 to Sites of DNA Damage
Greeson, N. T., Sengupta, R., Arida, A. R., Jenuwein, T., & Sanders, S. L. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m806857200 · Cited by 65 · see citing works
Degrees make all the difference: The multifunctionality of histone H4 lysine 20 methylation
Wang, Y., & Jia, S. (2009) · Epigenetics · doi:10.4161/epi.4.5.9212 · Cited by 59 · see citing works
Cdc13 Telomere Capping Decreases Mec1 Association but Does Not Affect Tel1 Association with DNA Ends
Hirano, Y., & Sugimoto, K. (2007) · Molecular Biology of the Cell · doi:10.1091/mbc.e06-12-1074 · Cited by 51 · see citing works
Regulation of checkpoint kinases through dynamic interaction with Crb2
Mochida, S., Esashi, F., Aono, N., Tamai, K., O’Connell, M. J., & Yanagida, M. (2004) · The EMBO Journal · doi:10.1038/sj.emboj.7600018 · Cited by 49 · see citing works
Khair, L., Subramanian, L., Moser, B. A., & Nakamura, T. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.078840 · Cited by 22 · see citing works
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Aging, Cellular Senescence, and Cancer
Campisi, J. (2013) · Annual Review of Physiology · doi:10.1146/annurev-physiol-030212-183653 · Cited by 2,954 · see citing works
The Telomere Deprotection Response Is Functionally Distinct from the Genomic DNA Damage Response
Cesare, A. J., Hayashi, M. T., Crabbe, L., & Karlseder, J. (2013) · Molecular Cell · doi:10.1016/j.molcel.2013.06.006 · Cited by 155 · see citing works
Gong, Y., & de Lange, T. (2010) · Molecular Cell · doi:10.1016/j.molcel.2010.10.016 · Cited by 102 · see citing works
- Authors
- Carneiro, T., Khair, L., Reis, C. C., Borges, V., Moser, B. A., Nakamura, T. M., & Ferreira, M. G.
- Affiliations
- Instituto Gulbenkian de Ciência (PT)
- University of Illinois Chicago (US)
- Corresponding author
- Ferreira, Miguel Godinho
- ORCID
- Venue
- Nature
- Published
- 2010-09
- Volume
- 467
- Issue
- 7312
- Pages
- 228-232
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC3196630
- OpenAlex
- W2024557782
- Cited by
- 75
- References
- 33
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 1 · 2023: 1 · 2022: 3 · 2021: 5 · 2020: 2 · 2019: 5 · 2018: 2 · 2017: 11 · 2016: 7 · 2015: 4 · 2014: 6 · 2013: 6 · 2012: 11
- FWCI
- 5.42
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Institute of General Medical Sciences (GM078253, R01GM078253)
- Topics
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA and Nucleic Acid Chemistry
- Keywords
- telomeres, telomere protection, DNA damage checkpoint, histone modifications, H3K9 dimethylation, POT1, Taz1, RAD51, RAD52, ATRIP, Chk1, cell cycle arrest
- MeSH terms
- Cell Cycle, DNA Damage, DNA Repair, Schizosaccharomyces, Signal Transduction, Telomere, Schizosaccharomyces pombe Proteins, Telomere-Binding Proteins
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