Oncogene-induced Telomere Dysfunction Enforces Cellular Senescence in Human Cancer Precursor Lesions

Overview

Journal EMBO J

Specialties Biotechnology
Molecular Biology

Date 2012 May 10

PMID 22569128

Citations 134

Authors

Anitha Suram

Jessica Kaplunov

Priyanka L Patel

Haihe Ruan

Aurora Cerutti

Virginia Boccardi

Marzia Fumagalli

Raffaella Di Micco

Neena Mirani

Resham Lal Gurung

Manoor Prakash Hande

Fabrizio dAdda di Fagagna

Utz Herbig

Affiliations

Soon will be listed here.

Abstract

In normal human somatic cells, telomere dysfunction causes cellular senescence, a stable proliferative arrest with tumour suppressing properties. Whether telomere dysfunction-induced senescence (TDIS) suppresses cancer growth in humans, however, is unknown. Here, we demonstrate that multiple and distinct human cancer precursor lesions, but not corresponding malignant cancers, are comprised of cells that display hallmarks of TDIS. Furthermore, we demonstrate that oncogenic signalling, frequently associated with initiating cancer growth in humans, dramatically affected telomere structure and function by causing telomeric replication stress, rapid and stochastic telomere attrition, and consequently telomere dysfunction in cells that lack hTERT activity. DNA replication stress induced by drugs also resulted in telomere dysfunction and cellular senescence in normal human cells, demonstrating that telomeric repeats indeed are hypersensitive to DNA replication stress. Our data reveal that TDIS, accelerated by oncogene-induced DNA replication stress, is a biological response of cells in human cancer precursor lesions and provide strong evidence that TDIS is a critical tumour suppressing mechanism in humans.

Citing Articles

Detecting Telomeric DNA Damage by Immuno-Telo FISH.

Paulis M, Garbarino O, Faggioli F Methods Mol Biol. 2025; 2906:137-147.

PMID: 40082354 DOI: 10.1007/978-1-0716-4426-3_8.

The relationship between telomere length and aging-related diseases.

Huang X, Huang L, Lu J, Cheng L, Wu D, Li L Clin Exp Med. 2025; 25(1):72.

PMID: 40044947 PMC: 11882723. DOI: 10.1007/s10238-025-01608-z.

Therapy-Induced Cellular Senescence: Potentiating Tumor Elimination or Driving Cancer Resistance and Recurrence?.

Liu Y, Lomeli I, Kron S Cells. 2024; 13(15.

PMID: 39120312 PMC: 11312217. DOI: 10.3390/cells13151281.

Senescent cell-derived vaccines: a new concept towards an immune response against cancer and aging?.

Pessoa J, Nobrega-Pereira S, de Jesus B Aging (Albany NY). 2024; 16(12):10657-10665.

PMID: 38942604 PMC: 11236300. DOI: 10.18632/aging.205975.

Replication stress as a driver of cellular senescence and aging.

Herr L, Schaffer E, Fuchs K, Datta A, Brosh Jr R Commun Biol. 2024; 7(1):616.

PMID: 38777831 PMC: 11111458. DOI: 10.1038/s42003-024-06263-w.

References

Hanahan D, Weinberg R . Hallmarks of cancer: the next generation. Cell. 2011; 144(5):646-74. DOI: 10.1016/j.cell.2011.02.013. View

Tuveson D, Shaw A, Willis N, Silver D, Jackson E, Chang S . Endogenous oncogenic K-ras(G12D) stimulates proliferation and widespread neoplastic and developmental defects. Cancer Cell. 2004; 5(4):375-87. DOI: 10.1016/s1535-6108(04)00085-6. View

Hahn W, Counter C, Lundberg A, Beijersbergen R, Brooks M, Weinberg R . Creation of human tumour cells with defined genetic elements. Nature. 1999; 400(6743):464-8. DOI: 10.1038/22780. View

Herbig U, Sedivy J . Regulation of growth arrest in senescence: telomere damage is not the end of the story. Mech Ageing Dev. 2005; 127(1):16-24. DOI: 10.1016/j.mad.2005.09.002. View

Martinez P, Thanasoula M, Munoz P, Liao C, Tejera A, McNees C . Increased telomere fragility and fusions resulting from TRF1 deficiency lead to degenerative pathologies and increased cancer in mice. Genes Dev. 2009; 23(17):2060-75. PMC: 2751970. DOI: 10.1101/gad.543509. View

Adams M, Carpenter P . Tying the loose ends together in DNA double strand break repair with 53BP1. Cell Div. 2006; 1:19. PMC: 1601952. DOI: 10.1186/1747-1028-1-19. View

Feldser D, Greider C . Short telomeres limit tumor progression in vivo by inducing senescence. Cancer Cell. 2007; 11(5):461-9. PMC: 1945093. DOI: 10.1016/j.ccr.2007.02.026. View

Lansdorp P . Major cutbacks at chromosome ends. Trends Biochem Sci. 2005; 30(7):388-95. DOI: 10.1016/j.tibs.2005.05.004. View

Courtois-Cox S, Jones S, Cichowski K . Many roads lead to oncogene-induced senescence. Oncogene. 2008; 27(20):2801-9. DOI: 10.1038/sj.onc.1210950. View

10.

Ye J, Lenain C, Bauwens S, Rizzo A, Saint-Leger A, Poulet A . TRF2 and apollo cooperate with topoisomerase 2alpha to protect human telomeres from replicative damage. Cell. 2010; 142(2):230-42. DOI: 10.1016/j.cell.2010.05.032. View

11.

Bandyopadhyay D, Curry J, Lin Q, Richards H, Chen D, Hornsby P . Dynamic assembly of chromatin complexes during cellular senescence: implications for the growth arrest of human melanocytic nevi. Aging Cell. 2007; 6(4):577-91. PMC: 1974778. DOI: 10.1111/j.1474-9726.2007.00308.x. View

12.

Abdallah P, Luciano P, Runge K, Lisby M, Geli V, Gilson E . A two-step model for senescence triggered by a single critically short telomere. Nat Cell Biol. 2009; 11(8):988-93. PMC: 4025917. DOI: 10.1038/ncb1911. View

13.

Bartkova J, Horejsi Z, Sehested M, Nesland J, Rajpert-De Meyts E, Skakkebaek N . DNA damage response mediators MDC1 and 53BP1: constitutive activation and aberrant loss in breast and lung cancer, but not in testicular germ cell tumours. Oncogene. 2007; 26(53):7414-22. DOI: 10.1038/sj.onc.1210553. View

14.

Herbig U, Jobling W, Chen B, Chen D, Sedivy J . Telomere shortening triggers senescence of human cells through a pathway involving ATM, p53, and p21(CIP1), but not p16(INK4a). Mol Cell. 2004; 14(4):501-13. DOI: 10.1016/s1097-2765(04)00256-4. View

15.

Takai H, Smogorzewska A, de Lange T . DNA damage foci at dysfunctional telomeres. Curr Biol. 2003; 13(17):1549-56. DOI: 10.1016/s0960-9822(03)00542-6. View

16.

Di Micco R, Fumagalli M, Cicalese A, Piccinin S, Gasparini P, Luise C . Oncogene-induced senescence is a DNA damage response triggered by DNA hyper-replication. Nature. 2006; 444(7119):638-42. DOI: 10.1038/nature05327. View

17.

Hao H, Muniz-Medina V, Mehta H, Thomas N, Khazak V, Der C . Context-dependent roles of mutant B-Raf signaling in melanoma and colorectal carcinoma cell growth. Mol Cancer Ther. 2007; 6(8):2220-9. DOI: 10.1158/1535-7163.MCT-06-0728. View

18.

Schultz L, Chehab N, Malikzay A, Halazonetis T . p53 binding protein 1 (53BP1) is an early participant in the cellular response to DNA double-strand breaks. J Cell Biol. 2001; 151(7):1381-90. PMC: 2150674. DOI: 10.1083/jcb.151.7.1381. View

19.

Fumagalli M, Rossiello F, Clerici M, Barozzi S, Cittaro D, Kaplunov J . Telomeric DNA damage is irreparable and causes persistent DNA-damage-response activation. Nat Cell Biol. 2012; 14(4):355-65. PMC: 3717580. DOI: 10.1038/ncb2466. View

20.

Kaul Z, Cesare A, Huschtscha L, Neumann A, Reddel R . Five dysfunctional telomeres predict onset of senescence in human cells. EMBO Rep. 2011; 13(1):52-9. PMC: 3246253. DOI: 10.1038/embor.2011.227. View