A Two-step Model for Senescence Triggered by a Single Critically Short Telomere

Overview

Journal Nat Cell Biol

Specialty Cell Biology

Date 2009 Jul 15

PMID 19597486

Citations 104

Authors

Pauline Abdallah

Pierre Luciano

Kurt W Runge

Michael Lisby

Vincent Geli

Eric Gilson

M Teresa Teixeira

Affiliations

Soon will be listed here.

Abstract

Telomeres protect chromosome ends from fusion and degradation. In the absence of a specific telomere elongation mechanism, their DNA shortens progressively with every round of replication, leading to replicative senescence. Here, we show that telomerase-deficient cells bearing a single, very short telomere senesce earlier, demonstrating that the length of the shortest telomere is a major determinant of the onset of senescence. We further show that Mec1p-ATR specifically recognizes the single, very short telomere causing the accelerated senescence. Strikingly, before entering senescence, cells divide for several generations despite complete erosion of their shortened telomeres. This pre-senescence growth requires RAD52 (radiation sensitive) and MMS1 (methyl methane sulfonate sensitive), and there is no evidence for major inter-telomeric recombination. We propose that, in the absence of telomerase, a very short telomere is first maintained in a pre-signalling state by a RAD52-MMS1-dependent pathway and then switches to a signalling state leading to senescence through a Mec1p-dependent checkpoint.

Citing Articles

Mathematical model linking telomeres to senescence in Saccharomyces cerevisiae reveals cell lineage versus population dynamics.

Rat A, Martinez Fernandez V, Doumic M, Teixeira M, Xu Z Nat Commun. 2025; 16(1):1024.

PMID: 39863614 PMC: 11762778. DOI: 10.1038/s41467-025-56196-z.

Integrated analysis of single-cell and bulk-RNA sequencing for the cellular senescence in prognosis of lung adenocarcinoma.

Yu F, Zhang L, Zhang X, Zeng J, Lai F Sci Rep. 2025; 15(1):1442.

PMID: 39789322 PMC: 11717922. DOI: 10.1038/s41598-025-85758-w.

Insights into the length and breadth of methodologies harnessed to study human telomeres.

Coulter T, Hill C, McKnight A Biomark Res. 2024; 12(1):127.

PMID: 39438947 PMC: 11515763. DOI: 10.1186/s40364-024-00668-9.

Roles of chromatin and genome instability in cellular senescence and their relevance to ageing and related diseases.

Wu Z, Qu J, Liu G Nat Rev Mol Cell Biol. 2024; 25(12):979-1000.

PMID: 39363000 DOI: 10.1038/s41580-024-00775-3.

High-throughput single telomere analysis using DNA microarray and fluorescent in situ hybridization.

Zheng Y, Wu X, Williams M, Verhulst S, Lin J, Takahashi Y Nucleic Acids Res. 2024; 52(19):e96.

PMID: 39291738 PMC: 11514468. DOI: 10.1093/nar/gkae812.

References

Mallory J, Petes T . Protein kinase activity of Tel1p and Mec1p, two Saccharomyces cerevisiae proteins related to the human ATM protein kinase. Proc Natl Acad Sci U S A. 2000; 97(25):13749-54. PMC: 17647. DOI: 10.1073/pnas.250475697. View

Schaetzlein S, Kodandaramireddy N, Ju Z, Lechel A, Stepczynska A, Lilli D . Exonuclease-1 deletion impairs DNA damage signaling and prolongs lifespan of telomere-dysfunctional mice. Cell. 2007; 130(5):863-77. PMC: 2658812. DOI: 10.1016/j.cell.2007.08.029. View

Arneric M, Lingner J . Tel1 kinase and subtelomere-bound Tbf1 mediate preferential elongation of short telomeres by telomerase in yeast. EMBO Rep. 2007; 8(11):1080-5. PMC: 2247385. DOI: 10.1038/sj.embor.7401082. View

Louis E . The chromosome ends of Saccharomyces cerevisiae. Yeast. 1995; 11(16):1553-73. DOI: 10.1002/yea.320111604. View

Marcand S, Gilson E, Shore D . A protein-counting mechanism for telomere length regulation in yeast. Science. 1997; 275(5302):986-90. DOI: 10.1126/science.275.5302.986. View

Duro E, Vaisica J, Brown G, Rouse J . Budding yeast Mms22 and Mms1 regulate homologous recombination induced by replisome blockage. DNA Repair (Amst). 2008; 7(5):811-8. DOI: 10.1016/j.dnarep.2008.01.007. View

Longhese M, Paciotti V, Neecke H, Lucchini G . Checkpoint proteins influence telomeric silencing and length maintenance in budding yeast. Genetics. 2000; 155(4):1577-91. PMC: 1461196. DOI: 10.1093/genetics/155.4.1577. View

Bianchi A, Shore D . Increased association of telomerase with short telomeres in yeast. Genes Dev. 2007; 21(14):1726-30. PMC: 1920167. DOI: 10.1101/gad.438907. View

Hemann M, Strong M, Hao L, Greider C . The shortest telomere, not average telomere length, is critical for cell viability and chromosome stability. Cell. 2001; 107(1):67-77. DOI: 10.1016/s0092-8674(01)00504-9. View

10.

Zaidi I, Rabut G, Poveda A, Scheel H, Malmstrom J, Ulrich H . Rtt101 and Mms1 in budding yeast form a CUL4(DDB1)-like ubiquitin ligase that promotes replication through damaged DNA. EMBO Rep. 2008; 9(10):1034-40. PMC: 2572122. DOI: 10.1038/embor.2008.155. View

11.

Decourty L, Saveanu C, Zemam K, Hantraye F, Frachon E, Rousselle J . Linking functionally related genes by sensitive and quantitative characterization of genetic interaction profiles. Proc Natl Acad Sci U S A. 2008; 105(15):5821-6. PMC: 2311358. DOI: 10.1073/pnas.0710533105. View

12.

Khadaroo B, Teixeira M, Luciano P, Eckert-Boulet N, Germann S, Simon M . The DNA damage response at eroded telomeres and tethering to the nuclear pore complex. Nat Cell Biol. 2009; 11(8):980-7. DOI: 10.1038/ncb1910. View

13.

Leroy C, Lee S, Vaze M, Ochsenbein F, Ochsenbien F, Guerois R . PP2C phosphatases Ptc2 and Ptc3 are required for DNA checkpoint inactivation after a double-strand break. Mol Cell. 2003; 11(3):827-35. DOI: 10.1016/s1097-2765(03)00058-3. View

14.

Lundblad V, Blackburn E . An alternative pathway for yeast telomere maintenance rescues est1- senescence. Cell. 1993; 73(2):347-60. DOI: 10.1016/0092-8674(93)90234-h. View

15.

Sandell L, Zakian V . Loss of a yeast telomere: arrest, recovery, and chromosome loss. Cell. 1993; 75(4):729-39. DOI: 10.1016/0092-8674(93)90493-a. View

16.

Teng S, Zakian V . Telomere-telomere recombination is an efficient bypass pathway for telomere maintenance in Saccharomyces cerevisiae. Mol Cell Biol. 1999; 19(12):8083-93. PMC: 84893. DOI: 10.1128/MCB.19.12.8083. View

17.

Teixeira M, Arneric M, Sperisen P, Lingner J . Telomere length homeostasis is achieved via a switch between telomerase- extendible and -nonextendible states. Cell. 2004; 117(3):323-35. DOI: 10.1016/s0092-8674(04)00334-4. View

18.

Tresaugues L, Dehe P, Guerois R, Rodriguez-Gil A, Varlet I, Salah P . Structural characterization of Set1 RNA recognition motifs and their role in histone H3 lysine 4 methylation. J Mol Biol. 2006; 359(5):1170-81. DOI: 10.1016/j.jmb.2006.04.050. View

19.

Marcand S, Brevet V, Gilson E . Progressive cis-inhibition of telomerase upon telomere elongation. EMBO J. 1999; 18(12):3509-19. PMC: 1171430. DOI: 10.1093/emboj/18.12.3509. View

20.

Enomoto S, Glowczewski L, Berman J . MEC3, MEC1, and DDC2 are essential components of a telomere checkpoint pathway required for cell cycle arrest during senescence in Saccharomyces cerevisiae. Mol Biol Cell. 2002; 13(8):2626-38. PMC: 117930. DOI: 10.1091/mbc.02-02-0012. View