Telomeres and telomerase in cancer.

Myriad genetic and epigenetic alterations are required to drive normal cells toward malignant transformation. These somatic events commandeer many signaling pathways that cooperate to endow aspiring cancer cells with a full range of biological capabilities needed to grow, disseminate and ultimately kill its host. Cancer genomes are highly rearranged and are characterized by complex translocations and regional copy number alterations that target loci harboring cancer-relevant genes. Efforts to uncover the underlying mechanisms driving genome instability in cancer have revealed a prominent role for telomeres. Telomeres are nucleoprotein structures that protect the ends of eukaryotic chromosomes and are particularly vulnerable due to progressive shortening during each round of DNA replication and, thus, a lifetime of tissue renewal places the organism at risk for increasing chromosomal instability. Indeed, telomere erosion has been documented in aging tissues and hyperproliferative disease states-conditions strongly associated with increased cancer risk. Telomere dysfunction can produce the opposing pathophysiological states of degenerative aging or cancer with the specific outcome dictated by the integrity of DNA damage checkpoint responses. In most advanced cancers, telomerase is reactivated and serves to maintain telomere length and emerging data have also documented the capacity of telomerase to directly regulate cancer-promoting pathways. This review covers the role of telomeres and telomerase in the biology of normal tissue stem/progenitor cells and in the development of cancer.

[1]  P. Armitage,et al.  The age distribution of cancer and a multi-stage theory of carcinogenesis , 1954, British Journal of Cancer.

[2]  L. Hayflick,et al.  The serial cultivation of human diploid cell strains. , 1961, Experimental cell research.

[3]  Robert A. Weinberg,et al.  Tumorigenic conversion of primary embryo fibroblasts requires at least two cooperating oncogenes , 1983, Nature.

[4]  Allan Balmain,et al.  Activation of the mouse cellular Harvey-ras gene in chemically induced benign skin papillomas , 1984, Nature.

[5]  E. Blackburn,et al.  A telomeric sequence in the RNA of Tetrahymena telomerase required for telomere repeat synthesis , 1989, Nature.

[6]  C. Harley,et al.  Telomeres shorten during ageing of human fibroblasts , 1990, Nature.

[7]  G. Wahl,et al.  A central role for chromosome breakage in gene amplification, deletion formation, and amplicon integration. , 1991, Genes & development.

[8]  E. Hara,et al.  Cooperative effect of antisense-Rb and antisense-p53 oligomers on the extension of life span in human diploid fibroblasts, TIG-1. , 1991, Biochemical and biophysical research communications.

[9]  J. Shay,et al.  A role for both RB and p53 in the regulation of human cellular senescence. , 1991, Experimental cell research.

[10]  J. Steitz,et al.  Telomere shortening associated with chromosome instability is arrested in immortal cells which express telomerase activity. , 1992, The EMBO journal.

[11]  L. Donehower,et al.  Spontaneous and carcinogen–induced tumorigenesis in p53–deficient mice , 1993, Nature Genetics.

[12]  R. Weinberg,et al.  Tumor spectrum analysis in p53-mutant mice , 1994, Current Biology.

[13]  H. Demura,et al.  Reduction of telomeric length and c‐erbb‐2 gene amplification in human breast cancer, fibroadenoma, and gynecomastia. Relationship to histologic grade and clinical parameters , 1994, Cancer.

[14]  C B Harley,et al.  Specific association of human telomerase activity with immortal cells and cancer. , 1994, Science.

[15]  S. Seki,et al.  Telomere shortening in chronic liver diseases. , 1995, Biochemical and Biophysical Research Communications - BBRC.

[16]  S. Gallinger,et al.  Telomerase activity associated with acquisition of malignancy in human colorectal cancer. , 1995, Cancer research.

[17]  F. Zindy,et al.  Alternative reading frames of the INK4a tumor suppressor gene encode two unrelated proteins capable of inducing cell cycle arrest , 1995, Cell.

[18]  L. Donehower,et al.  Effects of genetic background on tumorigenesis in p53‐deficient mice , 1995, Molecular carcinogenesis.

[19]  L. Chin,et al.  Role of the INK4a Locus in Tumor Suppression and Cell Mortality , 1996, Cell.

[20]  P. O'Connor,et al.  Cell Cycle Checkpoints and Cancer Chemotherapy , 1996 .

[21]  K. Nouso,et al.  Telomere length in human liver diseases. , 2008, Liver.

[22]  Richard A. Ashmun,et al.  Tumor Suppression at the Mouse INK4a Locus Mediated by the Alternative Reading Frame Product p19 ARF , 1997, Cell.

[23]  Wenyi Wei,et al.  Bypass of senescence after disruption of p21CIP1/WAF1 gene in normal diploid human fibroblasts. , 1997, Science.

[24]  María A Blasco,et al.  Telomere Shortening and Tumor Formation by Mouse Cells Lacking Telomerase RNA , 1997, Cell.

[25]  C B Harley,et al.  Telomerase catalytic subunit homologs from fission yeast and human. , 1997, Science.

[26]  June Corwin,et al.  Telomerase Catalytic Subunit Homologs from Fission Yeast and Human , 1997 .

[27]  J. Shay,et al.  Telomerase activity concentrates in the mitotically active segments of human hair follicles. , 1997, The Journal of investigative dermatology.

[28]  M. Oshimura,et al.  Progressive telomere shortening and telomerase reactivation during hepatocellular carcinogenesis. , 1997, Cancer genetics and cytogenetics.

[29]  R. Weinberg,et al.  hEST2, the Putative Human Telomerase Catalytic Subunit Gene, Is Up-Regulated in Tumor Cells and during Immortalization , 1997, Cell.

[30]  J. Guillem,et al.  Telomerase and telomere length in the development and progression of premalignant lesions to colorectal cancer. , 1997, Clinical cancer research : an official journal of the American Association for Cancer Research.

[31]  Bas van Steensel,et al.  Control of telomere length by the human telomeric protein TRF1 , 1997, Nature.

[32]  T R Hughes,et al.  Reverse transcriptase motifs in the catalytic subunit of telomerase. , 1997, Science.

[33]  Gregg B. Morin,et al.  Reconstitution of human telomerase with the template RNA component hTR and the catalytic protein subunit hTRT , 1997, Nature Genetics.

[34]  W. Hahn,et al.  Dissociation among in vitro telomerase activity, telomere maintenance, and cellular immortalization. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[35]  Bas van Steensel,et al.  TRF2 Protects Human Telomeres from End-to-End Fusions , 1998, Cell.

[36]  C. Harley,et al.  Extension of life-span by introduction of telomerase into normal human cells. , 1998, Science.

[37]  E. Fuchs,et al.  De Novo Hair Follicle Morphogenesis and Hair Tumors in Mice Expressing a Truncated β-Catenin in Skin , 1998, Cell.

[38]  Ken Chen,et al.  The Ink4a Tumor Suppressor Gene Product, p19Arf, Interacts with MDM2 and Neutralizes MDM2's Inhibition of p53 , 1998, Cell.

[39]  R. DePinho,et al.  Essential role of mouse telomerase in highly proliferative organs , 1998, Nature.

[40]  F. Zindy,et al.  Functional and physical interactions of the ARF tumor suppressor with p53 and Mdm2. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[41]  P. Lansdorp,et al.  Telomerase activity in candidate stem cells from fetal liver and adult bone marrow. , 1998, Blood.

[42]  Jeffrey B. Cheng,et al.  A Box H/ACA Small Nucleolar RNA-Like Domain at the Human Telomerase RNA 3′ End , 1999, Molecular and Cellular Biology.

[43]  R. Dalla‐Favera,et al.  Direct activation of TERT transcription by c-MYC , 1999, Nature Genetics.

[44]  M. Blasco,et al.  Disease states associated with telomerase deficiency appear earlier in mice with short telomeres , 1999, The EMBO journal.

[45]  K. Collins,et al.  A telomerase component is defective in the human disease dyskeratosis congenita , 1999, Nature.

[46]  M. Mattson,et al.  Anti-apoptotic Role of Telomerase in Pheochromocytoma Cells* , 1999, The Journal of Biological Chemistry.

[47]  Sandy Chang,et al.  Longevity, Stress Response, and Cancer in Aging Telomerase-Deficient Mice , 1999, Cell.

[48]  L. Chin,et al.  Short Dysfunctional Telomeres Impair Tumorigenesis in the INK4aΔ2/3 Cancer-Prone Mouse , 1999, Cell.

[49]  B. Levine,et al.  Constitutive and regulated expression of telomerase reverse transcriptase (hTERT) in human lymphocytes. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[50]  J. Campisi,et al.  TIN2, a new regulator of telomere length in human cells , 1999, Nature Genetics.

[51]  O. A. Bachor,et al.  Telomerase is active in normal gastrointestinal mucosa and not up-regulated in precancerous lesions , 1999, Journal of Cancer Research and Clinical Oncology.

[52]  Lynda Chin,et al.  E.: “A Summary of , 1968 .

[53]  M. Hande,et al.  Telomere Length Dynamics and Chromosomal Instability in Cells Derived from Telomerase Null Mice , 1999, The Journal of cell biology.

[54]  J. Griffith,et al.  Mammalian Telomeres End in a Large Duplex Loop , 1999, Cell.

[55]  Robert A. Weinberg,et al.  Creation of human tumour cells with defined genetic elements , 1999, Nature.

[56]  L. Chin,et al.  Telomerase reverse transcriptase gene is a direct target of c-Myc but is not functionally equivalent in cellular transformation , 1999, Oncogene.

[57]  D. Broccoli,et al.  p53- and ATM-dependent apoptosis induced by telomeres lacking TRF2. , 1999, Science.

[58]  M. Blasco,et al.  Telomerase-deficient mice with short telomeres are resistant to skin tumorigenesis , 2000, Nature Genetics.

[59]  W. Kuo,et al.  Quantitative mapping of amplicon structure by array CGH identifies CYP24 as a candidate oncogene , 2000, Nature Genetics.

[60]  Lynda Chin,et al.  Telomere dysfunction promotes non-reciprocal translocations and epithelial cancers in mice , 2000, Nature.

[61]  R. DePinho,et al.  Inhibition of experimental liver cirrhosis in mice by telomerase gene delivery. , 2000, Science.

[62]  Jiunn-Liang Chen,et al.  Secondary Structure of Vertebrate Telomerase RNA , 2000, Cell.

[63]  L. Chin,et al.  Telomere dysfunction impairs DNA repair and enhances sensitivity to ionizing radiation , 2000, Nature Genetics.

[64]  T. Lange,et al.  Identification of Human Rap1 Implications for Telomere Evolution , 2000, Cell.

[65]  B. van Steensel,et al.  Control of Human Telomere Length by TRF1 and TRF2 , 2000, Molecular and Cellular Biology.

[66]  R. DePinho,et al.  Telomere dysfunction and evolution of intestinal carcinoma in mice and humans , 2001, Nature Genetics.

[67]  D. Hanahan,et al.  Genome scanning with array CGH delineates regional alterations in mouse islet carcinomas , 2001, Nature Genetics.

[68]  L. Chin,et al.  Dual Inactivation of RB and p53 Pathways in RAS-Induced Melanomas , 2001, Molecular and Cellular Biology.

[69]  M. Blasco,et al.  Increased epidermal tumors and increased skin wound healing in transgenic mice overexpressing the catalytic subunit of telomerase, mTERT, in basal keratinocytes , 2001, The EMBO journal.

[70]  Margaret A. Strong,et al.  The Shortest Telomere, Not Average Telomere Length, Is Critical for Cell Viability and Chromosome Stability , 2001, Cell.

[71]  P. Baumann,et al.  Pot1, the Putative Telomere End-Binding Protein in Fission Yeast and Humans , 2001, Science.

[72]  W. Hahn,et al.  Human breast cancer cells generated by oncogenic transformation of primary mammary epithelial cells. , 2001, Genes & development.

[73]  T. Vulliamy,et al.  The RNA component of telomerase is mutated in autosomal dominant dyskeratosis congenita , 2001, Nature.

[74]  M. Blasco,et al.  Restoration of telomerase activity rescues chromosomal instability and premature aging in Terc−/− mice with short telomeres , 2001, EMBO reports.

[75]  Scott E Kern,et al.  Telomere shortening is nearly universal in pancreatic intraepithelial neoplasia. , 2002, The American journal of pathology.

[76]  S. Artandi.  Telomere shortening and cell fates in mouse models of neoplasia. , 2002, Trends in molecular medicine.

[77]  A. Jauch,et al.  DNA Ligase IV-Dependent NHEJ of Deprotected Mammalian Telomeres in G1 and G2 , 2002, Current Biology.

[78]  L. Chin,et al.  Telomere dysfunction provokes regional amplification and deletion in cancer genomes. , 2002, Cancer cell.

[79]  W. Gage,et al.  Telomere length assessment in human archival tissues: combined telomere fluorescence in situ hybridization and immunostaining. , 2002, The American journal of pathology.

[80]  J. Shay,et al.  Telomerase and differentiation in multicellular organisms: turn it off, turn it on, and turn it off again. , 2002, Differentiation; research in biological diversity.

[81]  J. Potter,et al.  Chromosomal instability in ulcerative colitis is related to telomere shortening , 2002, Nature Genetics.

[82]  F. Alt,et al.  Unrepaired DNA Breaks in p53-Deficient Cells Lead to Oncogenic Gene Amplification Subsequent to Translocations , 2002, Cell.

[83]  Robert A. Weinberg,et al.  Telomerase contributes to tumorigenesis by a telomere length-independent mechanism , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[84]  Stephen N. Jones,et al.  p53 mutant mice that display early ageing-associated phenotypes , 2002, Nature.

[85]  T. Lange,et al.  DNA Damage Foci at Dysfunctional Telomeres , 2003, Current Biology.

[86]  James M. Roberts,et al.  Telomerase modulates expression of growth-controlling genes and enhances cell proliferation , 2003, Nature Cell Biology.

[87]  I. Weissman,et al.  Telomerase is required to slow telomere shortening and extend replicative lifespan of HSCs during serial transplantation. , 2003, Blood.

[88]  N. Carter,et al.  A DNA damage checkpoint response in telomere-initiated senescence , 2003, Nature.

[89]  E. Fearon,et al.  Transient activation of beta -catenin signaling in cutaneous keratinocytes is sufficient to trigger the active growth phase of the hair cycle in mice. , 2003, Genes & development.

[90]  Jennifer Y. Zhang,et al.  NF-kappaB blockade and oncogenic Ras trigger invasive human epidermal neoplasia. , 2003, Nature.

[91]  R. DePinho,et al.  Telomere-based crisis: functional differences between telomerase activation and ALT in tumor progression. , 2003, Genes & development.

[92]  T. Lange,et al.  POT1 as a terminal transducer of TRF1 telomere length control , 2003, Nature.

[93]  Jennifer Y. Zhang,et al.  NF-κB blockade and oncogenic Ras trigger invasive human epidermal neoplasia , 2003, Nature.

[94]  M. Serafini,et al.  Plasma antioxidants from chocolate , 2003, Nature.

[95]  K. Chin,et al.  In situ analyses of genome instability in breast cancer , 2004, Nature Genetics.

[96]  Jun Qin,et al.  PTOP interacts with POT1 and regulates its localization to telomeres , 2004, Nature Cell Biology.

[97]  B. Chait,et al.  POT 1-interacting protein PIP 1 : a telomere length regulator that recruits POT 1 to the TIN 2 / TRF 1 complex , 2004 .

[98]  B. Shpitz,et al.  Telomerase activity in ductal carcinoma in situ of the breast , 1999, Breast Cancer Research and Treatment.

[99]  F. Watt,et al.  Transient activation of β-catenin signalling in adult mouse epidermis is sufficient to induce new hair follicles but continuous activation is required to maintain hair follicle tumours , 2004, Development.

[100]  A. D. De Marzo,et al.  Recent advances in telomere biology: implications for human cancer , 2004, Current opinion in oncology.

[101]  E. Montgomery,et al.  Telomere Length Abnormalities Occur Early in the Initiation of Epithelial Carcinogenesis , 2004, Clinical Cancer Research.

[102]  B. Chait,et al.  POT1-interacting protein PIP1: a telomere length regulator that recruits POT1 to the TIN2/TRF1 complex. , 2004, Genes & development.

[103]  Tamás Kiss,et al.  Human telomerase RNA and box H/ACA scaRNAs share a common Cajal body–specific localization signal , 2004, The Journal of cell biology.

[104]  R. Terns,et al.  Telomerase RNA accumulates in Cajal bodies in human cancer cells. , 2003, Molecular biology of the cell.

[105]  P. Argani,et al.  Telomere shortening occurs in subsets of normal breast epithelium as well as in situ and invasive carcinoma. , 2004, The American journal of pathology.

[106]  M. Lako,et al.  Overexpression of Telomerase Confers Growth Advantage, Stress Resistance, and Enhanced Differentiation of ESCs Toward the Hematopoietic Lineage , 2005, Stem cells.

[107]  G. Hammer,et al.  Urogenital and caudal dysgenesis in adrenocortical dysplasia (acd) mice is caused by a splicing mutation in a novel telomeric regulator. , 2005, Human molecular genetics.

[108]  W. Hahn,et al.  The telomerase reverse transcriptase regulates chromatin state and DNA damage responses. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[109]  T. Lange,et al.  Shelterin: the protein complex that shapes and safeguards human telomeres , 2005 .

[110]  J. Shay,et al.  POT1 protects telomeres from a transient DNA damage response and determines how human chromosomes end , 2005, The EMBO journal.

[111]  Yen-Pei Christy Chang,et al.  Haploinsufficiency of telomerase reverse transcriptase leads to anticipation in autosomal dominant dyskeratosis congenita. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[112]  Ruth I. Tennen,et al.  Conditional telomerase induction causes proliferation of hair follicle stem cells , 2005, Nature.

[113]  Angus I Lamond,et al.  Cajal bodies: a long history of discovery. , 2005, Annual review of cell and developmental biology.

[114]  M. Blasco,et al.  Effects of Telomerase and Telomere Length on Epidermal Stem Cell Behavior , 2005, Science.

[115]  Sun-Mi Park,et al.  Ubiquitin ligase MKRN1 modulates telomere length homeostasis through a proteolysis of hTERT. , 2005, Genes & development.

[116]  D. Pinkel,et al.  Array comparative genomic hybridization and its applications in cancer , 2005, Nature Genetics.

[117]  T. Lange,et al.  DNA processing is not required for ATM-mediated telomere damage response after TRF2 deletion , 2005, Nature Cell Biology.

[118]  T. Lange,et al.  Recent Expansion of the Telomeric Complex in Rodents: Two Distinct POT1 Proteins Protect Mouse Telomeres , 2006, Cell.

[119]  J. Deng,et al.  Pot1 Deficiency Initiates DNA Damage Checkpoint Activation and Aberrant Homologous Recombination at Telomeres , 2006, Cell.

[120]  Hong Jiang,et al.  Cdkn1a deletion improves stem cell function and lifespan of mice with dysfunctional telomeres without accelerating cancer formation , 2006, Nature Genetics.

[121]  R. Terns,et al.  Cell cycle-regulated trafficking of human telomerase to telomeres. , 2005, Molecular biology of the cell.

[122]  N. Sharpless,et al.  The Regulation of INK4/ARF in Cancer and Aging , 2006, Cell.

[123]  G. Tseng,et al.  Comparison of gene expression and DNA copy number changes in a murine model of lung cancer , 2006, Genes, chromosomes & cancer.

[124]  A. Multani,et al.  Telomere dysfunction suppresses spontaneous tumorigenesis in vivo by initiating p53‐dependent cellular senescence , 2007, EMBO reports.

[125]  Dan Liu,et al.  TPP1 is a homologue of ciliate TEBP-β and interacts with POT1 to recruit telomerase , 2007, Nature.

[126]  R. Terns,et al.  Non-coding RNAs: lessons from the small nuclear and small nucleolar RNAs , 2007, Nature Reviews Molecular Cell Biology.

[127]  N. Bache,et al.  Protein Composition of Catalytically Active Human Telomerase from Immortal Cells , 2007, Science.

[128]  D. Feldser,et al.  Short telomeres limit tumor progression in vivo by inducing senescence. , 2007, Cancer cell.

[129]  T. Cech,et al.  The POT1–TPP1 telomere complex is a telomerase processivity factor , 2007, Nature.

[130]  L. Chin,et al.  Chromosomally unstable mouse tumours have genomic alterations similar to diverse human cancers , 2007, Nature.

[131]  Sandy Chang,et al.  Dysfunctional telomeres activate an ATM‐ATR‐dependent DNA damage response to suppress tumorigenesis , 2007, The EMBO journal.

[132]  D. Carrasco,et al.  Ink4a/Arf tumor suppressor does not modulate the degenerative conditions or tumor spectrum of the telomerase-deficient mouse , 2007, Proceedings of the National Academy of Sciences.

[133]  Katarzyna Sikora,et al.  Human telomerase RNA accumulation in Cajal bodies facilitates telomerase recruitment to telomeres and telomere elongation. , 2007, Molecular cell.

[134]  T. Lange,et al.  Protection of telomeres through independent control of ATM and ATR by TRF2 and POT1 , 2007, Nature.

[135]  G. Hammer,et al.  Telomere protection by mammalian Pot1 requires interaction with Tpp1 , 2007, Nature Structural &Molecular Biology.

[136]  邓伟平,et al.  Dyskeratosis congenita , 2007 .

[137]  T. Vulliamy,et al.  Genetic heterogeneity in autosomal recessive dyskeratosis congenita with one subtype due to mutations in the telomerase-associated protein NOP10. , 2007, Human molecular genetics.

[138]  G. Hammer,et al.  Telomere protection by mammalian Pot1 requires interaction with Tpp1. , 2009, Nature structural & molecular biology.

[139]  P. Baumann,et al.  A RAP1/TRF2 complex inhibits nonhomologous end-joining at human telomeric DNA ends. , 2007, Molecular cell.

[140]  Stuart K. Kim,et al.  TERT Promotes Epithelial Proliferation through Transcriptional Control of a Myc- and Wnt-Related Developmental Program , 2008, PLoS genetics.

[141]  Wilhelm Palm,et al.  How shelterin protects mammalian telomeres. , 2008, Annual review of genetics.

[142]  T. Vulliamy,et al.  TINF2 mutations result in very short telomeres: analysis of a large cohort of patients with dyskeratosis congenita and related bone marrow failure syndromes , 2008, Blood.

[143]  J. Hoeijmakers,et al.  DNA damage and ageing: new-age ideas for an age-old problem , 2008, Nature Cell Biology.

[144]  S. Kyo,et al.  Understanding and exploiting hTERT promoter regulation for diagnosis and treatment of human cancers , 2008, Cancer science.

[145]  S. Lowe,et al.  Implications of cellular senescence in tissue damage response, tumor suppression, and stem cell biology. , 2008, Cold Spring Harbor symposia on quantitative biology.

[146]  T. Veenstra,et al.  Identification of ATPases Pontin and Reptin as Telomerase Components Essential for Holoenzyme Assembly , 2008, Cell.

[147]  Claire Heride,et al.  Telomeres: hallmarks of radiosensitivity. , 2008, Biochimie.

[148]  L. Zon,et al.  A Non-Canonical Function of Zebrafish Telomerase Reverse Transcriptase Is Required for Developmental Hematopoiesis , 2008, PloS one.

[149]  Gerald C. Chu,et al.  P53 and Pten control neural and glioma stem/progenitor cell renewal and differentiation , 2008, Nature.

[150]  M. Lako,et al.  A Key Role for Telomerase Reverse Transcriptase Unit in Modulating Human Embryonic Stem Cell Proliferation, Cell Cycle Dynamics, and In Vitro Differentiation , 2008, Stem cells.

[151]  B. Thiers.  Induction of Pluripotent Stem Cells from Adult Human Fibroblasts by Defined Factors , 2008 .

[152]  N. Orr,et al.  TINF2, a component of the shelterin telomere protection complex, is mutated in dyskeratosis congenita. , 2008, American journal of human genetics.

[153]  H. K. Jeon,et al.  TERT promotes cellular and organismal survival independently of telomerase activity , 2008, Oncogene.

[154]  A. Wagers,et al.  Generation of mTert-GFP mice as a model to identify and study tissue progenitor cells , 2008, Proceedings of the National Academy of Sciences.

[155]  T. Vulliamy,et al.  Mutations in the telomerase component NHP2 cause the premature ageing syndrome dyskeratosis congenita , 2008, Proceedings of the National Academy of Sciences.

[156]  R. Kuick,et al.  Genetic p53 deficiency partially rescues the adrenocortical dysplasia phenotype at the expense of increased tumorigenesis. , 2009, Cancer cell.

[157]  W. Song,et al.  Telomerase deficiency and telomere dysfunction inhibit mammary tumors induced by polyomavirus middle T oncogene , 2009, Oncogene.

[158]  P. Baumann,et al.  Human RAP1 inhibits non‐homologous end joining at telomeres , 2009, The EMBO journal.

[159]  C. Schildkraut,et al.  Mammalian Telomeres Resemble Fragile Sites and Require TRF1 for Efficient Replication , 2009, Cell.

[160]  J. Steitz,et al.  A conserved WD40 protein binds the Cajal body localization signal of scaRNP particles. , 2009, Molecular cell.

[161]  M. Armanios.  Syndromes of telomere shortening. , 2009, Annual review of genomics and human genetics.

[162]  Timothy D. Veenstra,et al.  A Human Telomerase Holoenzyme Protein Required for Cajal Body Localization and Telomere Synthesis , 2009, Science.

[163]  R. DePinho,et al.  Dissecting genetic requirements of human breast tumorigenesis in a tissue transgenic model of human breast cancer in mice , 2009, Proceedings of the National Academy of Sciences.

[164]  W. Hahn,et al.  An RNA dependent RNA polymerase formed by hTERT and the RNase MRP RNA , 2009, Nature.

[165]  C. Vlangos,et al.  Caudal regression in adrenocortical dysplasia (acd) mice is caused by telomere dysfunction with subsequent p53-dependent apoptosis. , 2009, Developmental biology.

[166]  Sui Huang.  Faculty Opinions recommendation of An RNA-dependent RNA polymerase formed by TERT and the RMRP RNA. , 2009 .

[167]  Timothy D. Veenstra,et al.  Telomerase modulates Wnt signalling by association with target gene chromatin , 2009, Nature.