P16INK4a protects against dysfunctional telomere-induced ATR-dependent DNA damage responses

Journal of Clinical Investigation

Volumn 123, Issue 10, 2013, Pages 4489-4501

  Wang, Yang ^a   Sharpless, Norman ^b   Chang, Sandy ^a  

^a YALE UNIVERSITY SCHOOL OF MEDICINE   (United States)

^b UNIVERSITY OF NORTH CAROLINA SCHOOL OF MEDICINE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

CYCLIN DEPENDENT KINASE INHIBITOR 2A; PROTEIN P21; PROTEIN P53; ATM PROTEIN; ATR PROTEIN, MOUSE; CDKN2A PROTEIN, MOUSE; CYCLIN DEPENDENT KINASE INHIBITOR 1A; DNA BINDING PROTEIN; POT1B PROTEIN, MOUSE;

ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; APOPTOSIS; ARTICLE; CELL CYCLE ARREST; CELL PROLIFERATION; CHROMOSOME ABERRATION; CONTROLLED STUDY; DNA DAMAGE; FEMALE; GENE DELETION; GENOTYPE; HAPLOINSUFFICIENCY; HEMATOPOIETIC CELL; HEMATOPOIETIC SYSTEM; IN VIVO STUDY; LIFESPAN; MALE; MOUSE; NONHUMAN; PHENOTYPE; PRIORITY JOURNAL; PROTEIN EXPRESSION; PROTEIN FUNCTION; SENESCENCE; SMALL INTESTINE; TELOMERE; TESTIS; AGING; ANIMAL; BONE MARROW TRANSPLANTATION; CELL CULTURE; DNA REPAIR; GENETICS; HEMATOPOIESIS; HEMATOPOIETIC STEM CELL; METABOLISM; PATHOLOGY; PHYSIOLOGY; PROTEIN STABILITY; SCID MOUSE; SPLEEN; TELOMERE HOMEOSTASIS; TRANSGENIC MOUSE;

AGING; ANIMALS; APOPTOSIS; ATAXIA TELANGIECTASIA MUTATED PROTEINS; BONE MARROW TRANSPLANTATION; CELL PROLIFERATION; CELLS, CULTURED; CYCLIN-DEPENDENT KINASE INHIBITOR P16; CYCLIN-DEPENDENT KINASE INHIBITOR P21; DNA DAMAGE; DNA REPAIR; DNA-BINDING PROTEINS; FEMALE; HEMATOPOIESIS; HEMATOPOIETIC STEM CELLS; INTESTINE, SMALL; MALE; MICE; MICE, SCID; MICE, TRANSGENIC; PROTEIN STABILITY; SEQUENCE DELETION; SPLEEN; TELOMERE; TELOMERE HOMEOSTASIS; TUMOR SUPPRESSOR PROTEIN P53;

EID: 84885069619     PISSN: 00219738     EISSN: 15588238     Source Type: Journal    
DOI: 10.1172/JCI69574     Document Type: Article

References (64)

1. O'Sullivan RJ, Karlseder J. Telomeres: protecting chromosomes against genome instability. Nat Rev Mol Cell Biol. 2012;11(3):171-181.
2. Palm W, de Lange T. How shelterin protects mammalian telomeres. Annu Rev Genet. 2008;42:301-334.
3. Chan SS, Chang S. Defending the end zone: studying the players involved in protecting chromosome ends. FEBS Lett. 2010;584(17):3773-3778.
4. Boultwood J, et al. Telomere length in myelodysplastic syndromes. Am J Hematol. 1997;56(4):266-271.
5. Calado RT, Young NS. Telomere maintenance and human bone marrow failure. Blood. 2008;111(9):4446-4455.
6. Savage SA, Giri N, Baerlocher GM, Orr N, Lansdorp PM, Alter BP. TINF2, a component of the shelterin telomere protection complex, is mutated in dyskeratosis congenita. Am J Hum Genet. 2008;82(2):501-509.
7. Walne AJ, Vulliamy T, Beswick R, Kirwan M, Dokal I. TINF2 mutations result in very short telomeres: analysis of a large cohort of patients with dyskeratosis congenita and related bone marrow failure syndromes. Blood. 2008;112(9):3594-3600.
8. Deng Y, Guo X, Ferguson DO, Chang S. Multiple roles for MRE11 at uncapped telomeres. Nature. 2009;460(7257):914-918.
9. Dimitrova N, de Lange T. Cell cycle-dependent role of MRN at dysfunctional telomeres: ATM signaling-dependent induction of nonhomologous end joining (NHEJ) in G1 and resection-mediated inhibition of NHEJ in G2. Mol Cell Biol. 2009;29(20):5552-5563.
10. Cortez D, Guntuku S, Qin J, Elledge SJ. ATR and ATRIP: partners in checkpoint signaling. Science. 2001;294(5547):1713-1716.
11. Abraham RT. Cell cycle checkpoint signaling through the ATM and ATR kinases. Genes Dev. 2001;15(17):2177-2196.
12. Denchi EL, de Lange T. Protection of telomeres through independent control of ATM and ATR by TRF2 and POT1. Nature. 2007;448(7157):1068-1071.
13. Guo X, et al. Dysfunctional telomeres activate an ATM-ATR-dependent DNA damage response to suppress tumorigenesis. EMBO J. 2007;26(22):4709-4719.
14. Dimitrova N, de Lange T. Cell cycle-dependent role of MRN at dysfunctional telomeres: ATM signaling-dependent induction of nonhomologous end joining (NHEJ) in G1 and resection-mediated inhibition of NHEJ in G2. Mol Cell Biol. 2009;29(20):5552-5563.
15. Rai R, et al. The E3 ubiquitin ligase Rnf8 stabilizes Tpp1 to promote telomere end protection. Nat Struct Mol Biol. 2011;18(12):1400-4007.
16. Flynn RL, et al. TERRA and hnRNPA1 orchestrate an RPA-to-POT1 switch on telomeric single-stranded DNA. Nature. 2011;471(7339):532-536.
17. Wu L, et al. Pot1 deficiency initiates DNA damage checkpoint activation and aberrant homologous recombination at telomeres. Cell. 2006;126(1):49-62.
18. Palm W, Hockemeyer D, Kibe T, de Lange T. Functional dissection of human and mouse POT1 proteins. Mol Cell Biol. 2009;29(2):471-482.
19. He H, et al. POT1b protects telomeres from end-toend chromosomal fusions and aberrant homologous recombination. EMBO J. 2006;25(21):5180-5190.
20. Kibe T, Osawa GA, Keegan CE, de Lange T. Telomere protection by TPP1 is mediated by POT1a and POT1b. Mol Cell Biol. 2010;30(4):1059-1066.
21. Lam YC, et al. SNMIB/Apollo protects leading-strand telomeres against NHEJ-mediated repair. EMBO J. 2010;29(13):2230-2241.
22. Wu P, Takai H, de Lange T. Telomeric 3' overhangs derive from resection by Exo1 and Apollo and fill-in by POT1b-associated CST. Cell. 2012;150(1):39-52.
23. Rai R, et al. The function of classical and alternative non-homologous end-joining pathways in the fusion of dysfunctional telomeres. EMBO J. 2010;29(15):2598-2610.
24. Brown JP, Wei W, Sedivy JM. Bypass of senescence after disruption of p21CIP1/WAF1 gene in normal diploid human fibroblasts. Science. 1997;277(5327):831-834.
25. d'Adda di Fagagna F, et al. A DNA damage checkpoint response in telomere-initiated senescence. Nature. 2003;426(6963):194-198.
26. Herbig U, Jobling WA, Chen BP, Chen DJ, Sedivy JM. 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):501-513.
27. Cosme-Blanco W, et al. Telomere dysfunction suppresses spontaneous tumorigenesis in vivo by initiating p53-dependent cellular senescence. EMBO Rep. 2007;8(5):497-503.
28. Feldser DM, Greider CW. Short telomeres limit tumor progression in vivo by inducing senescence. Cancer Cell. 2007;11(5):461-469.
29. He H, et al. Pot1b deletion and telomerase haploinsufficiency in mice initiate an ATR-dependent DNA damage response and elicit phenotypes resembling dyskeratosis congenita. Mol Cell Biol. 2009;29(1):229-240.
30. Wang Y, Shen MF, Chang S. Essential roles for Pot1b in HSC self-renewal and survival. Blood. 2011;118(23):6068-6077.
31. Deng Y, Chan SS, Chang S. Telomere dysfunction and tumour suppression: the senescence connection. Nat Rev Cancer. 2008;8(6):450-458.
32. Rudolph KL, et al. Longevity, stress response, and cancer in aging telomerase-deficient mice. Cell. 1999;96(5):701-712.
33. Artandi SE, et al. Telomere dysfunction promotes non-reciprocal translocations and epithelial cancers in mice. Nature. 2000;406(6796):641-645.
34. Shay JW, Pereira-Smith OM, Wright WE. A role for both RB and p53 in the regulation of human cellular senescence. Exp Cell Res. 1991;196(1):33-39.
35. Jacobs JJ, de Lange T. Significant role for p16INK4a in p53-independent telomere-directed senescence. Curr Biol. 2004;14(24):2302-2308.
36. Janzen V, et al. Stem-cell ageing modified by the cyclin-dependent kinase inhibitor p16INK4a. Nature. 2006;443(7110):421-426.
37. Krishnamurthy J, et al. p16INK4a induces an age-dependent decline in islet regenerative potential. Nature. 2006;443(7110):453-457.
38. Molofsky AV, et al. Increasing p16INK4a expression decreases forebrain progenitors and neurogenesis during ageing. Nature. 2006;443(7110):448-452.
39. Liu Y, et al. Expression of p16 (INK4a) prevents cancer and promotes aging in lymphocytes. Blood. 2011;117(12):3257-3267.
40. Ito K, et al. Regulation of oxidative stress by ATM is required for self-renewal of haematopoietic stem cells. Nature. 2004;431(7011):997-1002.
41. Baker DJ, et al. Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature. 2011;479(7372):232-236.
42. Khoo CM, Carrasco DR, Bosenberg MW, Paik JH, Depinho RA. Ink4a/Arf tumor suppressor does not modulate the degenerative conditions or tumor spectrum of the telomerase-deficient mouse. Proc Natl Acad Sci U S A. 2007;104(10):3931- 3936.
43. Smogorzewska A, de Lange T. Different telomere damage signaling pathways in human and mouse cells. EMBO J. 2002;21(16):4338-4348.
44. Sfeir A, et al. Mammalian telomeres resemble fragile sites and require TRF1 for efficient replication. Cell. 2009;138(1):90-103.
45. Martinez P, et al. Increased telomere fragility and fusions resulting from TRF1 deficiency lead to degenerative pathologies and increased cancer in mice. Genes Dev. 2009;23(17):2060-2075.
46. Gu P, et al. CTC1 deletion results in defective telomere replication, leading to catastrophic telomere loss and stem cell exhaustion. EMBO J. 2012;31(10):2309-2321.
47. Bartkova J, et al. Oncogene-induced senescence is part of the tumorigenesis barrier imposed by DNA damage checkpoints. Nature. 2006;444(7119):633-637.
48. Lakin ND, Jackson SP. Regulation of p53 in response to DNA damage. Oncogene. 1999;18(53):7644-7655.
49. Bester AC, et al. Nucleotide deficiency promotes genomic instability in early stages of cancer development. Cell. 2011;145(3):435-446.
50. Krishnamurthy J, et al. Ink4a/Arf expression is a biomarker of aging. J Clin Invest. 2004;114(9):1299-1307.
51. Burd CE, et al. Monitoring tumorigenesis and senescence in vivo with a p16 (INK4a)-luciferase model. Cell. 2013;152(1-2):340-351.
52. Matheu A, et al. Anti-aging activity of the Ink4/Arf locus. Aging Cell. 2009;8(2):152-161.
53. Lukas J, et al. Retinoblastoma-protein-dependent cell-cycle inhibition by the tumour suppressor p16. Nature. 1995;375(6531):503-506.
54. Medema RH, Herrera RE, Lam F, Weinberg RA. Growth suppression by p16ink4 requires functional retinoblastoma protein. Proc Natl Acad Sci U S A. 1995;92(14):6289-6293.
55. Serrano M, Lee H, Chin L, Cordon-Cardo C, Beach D, DePinho RA. Role of the INK4a locus in tumor suppression and cell mortality. Cell. 1996;85(1):27-37.
56. Carnevale J, Palander O, Seifried LA, Dick FA. DNA damage signals through differentially modified E2F1 molecules to induce apoptosis. Mol Cell Biol. 2012;32(5):900-912.
57. Hershko T, Ginsberg D. Up-regulation of Bcl-2 homology 3 (BH3)-only proteins by E2F1 mediates apoptosis. J Biol Chem. 2004;279(10):8627-8634.
58. Braig M, et al. Oncogene-induced senescence as an initial barrier in lymphoma development. Nature. 2005;436(7051):660-665.
59. Michaloglou C, et al. BRAFE600-associated senescence-like cell cycle arrest of human naevi. Nature. 2005;436(7051):720-724.
60. Sherr CJ, McCormick F. The RB and p53 pathways in cancer. Cancer Cell. 2002;2(2):103-112.
61. Suh YA, et al. Multiple stress signals activate mutant p53 in vivo. Cancer Res. 2011;71(23):7168-7175.
62. Kim WY, Sharpless NE. The regulation of INK4/ARF in cancer and aging. Cell. 2006;127(2):265-275.
63. Choudhury AR, et al. Cdkn1a deletion improves stem cell function and lifespan of mice with dysfunctional telomeres without accelerating cancer formation. Nat Genet. 2007;39(1):99-105.
64. Sharpless NE, et al. Loss of p16Ink4a with retention of p19Arf predisposes mice to tumorigenesis. Nature. 2001;413(6851):86-91.