Increased telomere fragility and fusions resulting from TRF1 deficiency lead to degenerative pathologies and increased cancer in mice.
The telomere repeat-binding factor 1 (TERF1, referred to hereafter as TRF1) is a component of mammalian telomeres whose role in telomere biology and disease has remained elusive. Here, we report on cells and mice conditionally deleted for TRF1. TRF1-deleted mouse embryonic fibroblasts (MEFs) show rapid induction of senescence, which is concomitant with abundant telomeric gamma-H2AX foci and activation of the ATM/ATR downstream checkpoint kinases CHK1 and CHK2. DNA damage foci are rescued by both ATM and ATM/ATR inhibitors, further indicating that both signaling pathways are activated upon TRF1 deletion. Abrogation of the p53 and RB pathways bypasses senescence but leads to chromosomal instability including sister chromatid fusions, chromosome concatenation, and occurrence of multitelomeric signals (MTS). MTS are also elevated in ATR-deficient MEFs or upon treatment with aphidicolin, two conditions known to induce breakage at fragile sites, suggesting that TRF1-depleted telomeres are prone to breakage. To address the impact of these molecular defects in the organism, we deleted TRF1 in stratified epithelia of TRF1(Delta/Delta)K5-Cre mice. These mice die perinatally and show skin hyperpigmentation and epithelial dysplasia, which are associated with induction of telomere-instigated DNA damage, activation of the p53/p21 and p16 pathways, and cell cycle arrest in vivo. p53 deficiency rescues mouse survival but leads to development of squamous cell carcinomas, demonstrating that TRF1 suppresses tumorigenesis. Together, these results demonstrate that dysfunction of a telomere-binding protein is sufficient to produce severe telomeric damage in the absence of telomere shortening, resulting in premature tissue degeneration and development of neoplastic lesions.
Martínez
Paula
P
Telomeres and Telomerase Group, Molecular Oncology Program, Spanish National Cancer Centre (CNIO), Madrid E-28029, Spain.
Thanasoula
Maria
M
Muñoz
Purificación
P
Liao
Chunyan
C
Tejera
Agueda
A
McNees
Carolyn
C
Flores
Juana M
JM
Fernández-Capetillo
Oscar
O
Tarsounas
Madalena
M
Blasco
Maria A
MA
D000375:Aging / Q000378:metabolism; D000818:Animals; D002453:Cell Cycle / Q000502:physiology; D002460:Cell Line; D002873:Chromosome Fragility; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004249:DNA Damage / Q000235:genetics; D050687:E2F1 Transcription Factor / Q000378:metabolism; D000078404:Epidermal Cells; D004817:Epidermis / Q000473:pathology; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D005786:Gene Expression Regulation; D017495:Hyperpigmentation / Q000209:etiology / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation / Q000235:genetics; D009363:Neoplasm Proteins / Q000378:metabolism; D009369:Neoplasms / Q000235:genetics; D011488:Protein Deficiency / Q000150:complications*; D012871:Skin Diseases / Q000209:etiology* / Q000235:genetics; D012878:Skin Neoplasms / Q000209:etiology* / Q000235:genetics; D013234:Stem Cells / Q000473:pathology; D016615:Telomere / Q000235:genetics*; D035321:Telomeric Repeat Binding Protein 1 / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D050759:Cyclin-Dependent Kinase Inhibitor p21; D050687:E2F1 Transcription Factor; D009363:Neoplasm Proteins; D035321:Telomeric Repeat Binding Protein 1; D016159:Tumor Suppressor Protein p53
Nat Genet. 2009 Aug;41(8):891-8
19620979
EMBO Rep. 2002 Nov;3(11):1055-61
12393752
Cell. 2006 Jul 14;126(1):63-77
16839877
Nat Genet. 1997 Oct;17(2):231-5
9326950
Cancer Sci. 2007 Jun;98(6):850-7
17433040
Cell. 2009 Apr 17;137(2):247-58
19361851
Cell. 2009 Jul 10;138(1):90-103
19596237
J Virol. 1986 Oct;60(1):290-3
3018293
Annu Rev Genet. 2007;41:169-92
17608616
Nat Genet. 1997 Oct;17(2):236-9
9326951
Mol Cell Biol. 2000 Nov;20(22):8602-12
11046155
N Engl J Med. 2007 Mar 29;356(13):1317-26
17392301
Mol Cell Biol. 2002 May;22(10):3474-87
11971978
Nat Genet. 2000 Jun;25(2):139-40
10835623
Nature. 2003 Jun 26;423(6943):1013-8
12768206
J Invest Dermatol. 1989 Dec;93(6):728-38
2479695
J Biol Chem. 2008 Aug 29;283(35):23981-8
18587156
Nat Genet. 2005 Oct;37(10):1063-71
16142233
Curr Biol. 2003 Sep 2;13(17):1549-56
12956959
Genes Dev. 2008 Mar 1;22(5):654-67
18283121
Nature. 1997 Feb 20;385(6618):740-3
9034193
Nat Cell Biol. 2005 Jul;7(7):712-8
15968270
Mol Cell. 2003 Dec;12(6):1489-98
14690602
Mol Cell Biol. 2000 Mar;20(5):1659-68
10669743
Curr Biol. 2005 Aug 9;15(15):1340-51
16085486
Nature. 2001 Sep 27;413(6854):432-5
11574891
Nat Cell Biol. 2008 Feb;10(2):228-36
18157120
Nat Genet. 2007 Jan;39(1):99-105
17143283
J Biol Chem. 2004 Dec 3;279(49):51338-42
15383534
Differentiation. 1994 Nov;58(1):53-64
7532601
Genes Dev. 2005 Sep 15;19(18):2100-10
16166375
EMBO J. 2001 Jun 1;20(11):2844-56
11387217
Proc Natl Acad Sci U S A. 2007 May 1;104(18):7552-7
17460043
Mol Cell Biol. 2002 Jan;22(1):332-42
11739745
Science. 1998 Nov 20;282(5393):1484-7
9822378
Nature. 2007 Aug 16;448(7155):820-3
17671506
Proc Natl Acad Sci U S A. 1987 Apr;84(8):2302-6
2436229
Proc Natl Acad Sci U S A. 1997 Jul 8;94(14):7400-5
9207103
J Invest Dermatol. 2003 Nov;121(5):963-8
14708593
Oncogene. 2003 Feb 27;22(8):1115-23
12606939
Cell. 1997 Oct 3;91(1):25-34
9335332
Nature. 1999 Dec 2;402(6761):551-5
10591218
Genes Dev. 2006 Oct 1;20(19):2648-53
17015429
EMBO J. 2007 Nov 28;26(23):4867-78
17962804
Mol Cell Biol. 2009 Jan;29(1):229-40
18936156
Genes Dev. 2007 Jan 15;21(2):206-20
17234886
Nature. 2005 Aug 4;436(7051):642
16079833
Cell. 1998 Feb 6;92(3):401-13
9476899
Cancer Cell. 2007 May;11(5):461-9
17433785
Cell. 2006 Jul 14;126(1):49-62
16839876
EMBO Rep. 2000 Sep;1(3):244-52
11256607
Science. 2002 Apr 19;296(5567):550-3
11910072
Cell Stem Cell. 2008 Jul 3;3(1):33-43
18593557
Science. 2005 Aug 19;309(5738):1253-6
16037417
Genes Dev. 2008 Jul 1;22(13):1773-85
18550783
Science. 2004 Apr 2;304(5667):97-100
15064417
Mol Cell Biol. 2009 Mar;29(6):1608-25
19124610
Mol Cell Biol. 2003 Sep;23(18):6533-41
12944479
Nature. 2003 Nov 13;426(6963):194-8
14608368