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Sandy Chang

MD, PhD, BS
Yale College Associate Dean for Science & Quantitative Reasoning Education, Professor of Laboratory Medicine, Pathology and Molecular Biophysics and Biochemistry; Associate Director, Molecular Diagnostics Laboratory

Contact Information

Sandy Chang, MD, PhD, BS

Mailing Address

  • Laboratory Medicine

    PO Box 208035

    New Haven, CT 06520-8035

    United States

Yale Medicine

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Research Summary

Dr. Chang has a strong track record in implementing tools and techniques, including the use of mouse genetics and cell biology approaches, to address the questions in telomere biology. Dr. Chang has been an active contributor for over a decade in how telomeres, repetitive sequences that cap the ends of eukaryotic chromosomes, protect chromosomal ends from being recognized as damaged DNA. Using mouse knockout technology and cellular/biochemical studies, his laboratory has previously demonstrated that single-strand telomere binding proteins protect chromosome ends from initiating a DNA damage response (DDR). In particular, his lab discovered that the Protection of Telomere 1a (Pot1a) protein plays an important role to protect telomeres from engaging an ATR-dependent DDR, which initiates p53 dependent apoptosis and/or cellular senescence. His lab also discovered that Pot1b, the second Pot1 ortholog in the mouse genome, is required for stem cell proliferation. The Pot1b conditional knockout mouse recapitulates many salient features of human bone marrow (BM) failure syndromes, and will be used to understand what roles dysfunctional telomeres play in the pathogenesis of BM failure. The Chang lab is also generating additional novel mouse models to understand mechanistically how dysfunctional telomeres activate apoptotic and/or cellular senescence pathways to suppress hematopoietic stem cell proliferation commonly observed in BM failure.

Extensive Research Description

Dr. Chang’s research program focuses on telomeres,repetitive DNA sequences at the ends of chromosomes critically important for the maintenance of genome stability. Perturbation of telomere length results in telomere dysfunction, leading to increased genomic instability that can promote early aging and cancer development. Dr. Chang’s laboratory was the first togenerate a faithful mouse model of Werner Syndrome (WS). This rare disease strikes individuals in their 30s and is marked by the development of aging phenotypes and early onset of cancer.

Dr. Chang found that when WRN deficiency is coupled withtelomere dysfunction, the combination increases genomic instability, pre-matureaging and increased tumorigenesis. In addition, his findings conclusively demonstrate that telomere status plays an important role in the development of premature aging pathologies observed in WS patients. With this mouse model, Dr. Chang's laboratory has also identified common genetic pathways that unify aging and cancer development. His laboratory was the first to show that WRN plays a critical role in preventing telomeres from undergoing aberrant homologous recombination. In the absence of both telomerase and WRN, telomeres readily undergo homologous recombination to generate long telomeres, activating an Alternative lengthening of Telomeres (ALT) phenotype that contributes to tumor formation. Dr. Chang’s findings thus shed light on the important link between aging and cancer by suggesting that WRN plays an important role in both of these processes.

Dr. Chang then went on to decipher the molecular mechanisms of how telomere dysfunction initiates premature aging phenotypes in the laboratory mouse. Dr. Chang's laboratory recently discovered that the POT1 (Protection of Telomere 1) protein is an integral member of a protein complex that binds to telomeres and is essential for the maintenance of telomere stability. Using homologous recombination, hislaboratory conditionally deleted POT 1 from the mouse genome and discovered that chromosomes became highly unstable. These results indicate that POT1 is normally required to suppress genomic instability by preventing the formation of dysfunctional telomeres. Importantly, loss of POT1 potently activates a DNA damage pathway that results in rapid onset of cellular senescence. In p53 null cells, this elevated genomic instability promotes malignant transformation and rapid onset of cancer. These important results suggest that dysfunctional telomeres could either suppress tumorigenesis by initiating cellular senescence (in the setting of an intact p53 pathway), or promote cancer through elevated genomic instability (in the setting of p53 deficiency). Dr. Chang is currently using this novel mouse model to explore the roles that cellular senescence play in initiating premature aging phenotypes in highly proliferative organs, including the intestine and hematopoietic systems.

Dr. Chang then proceeded to address a long standing question in the telomere field-is cellular senescence capable of suppress tumorigenesis in vivo? While apoptosis clearly has a tumor suppressive role in vivo, until recently it was not clear whether p53-dependent cellular senescence plays anyrole in tumor suppression in vivo. Usingclever mouse genetics, Dr. Chang’s laboratory generated mouse models with dysfunctional telomeres and a knock-in p53 allele that is able to activatecellular senescence but not apoptosis. His laboratory demonstrated for the first time that activation of cellular senescence by dysfunctional telomeres in mice potently suppressed tumorinitiation. Interestingly, while these mice did not succumb to cancer, many dieearly from cellular defects resembling advanced aging. These results suggest that initiation of telomere dysfunction in vivo compromises cellular renewal, resulting in the onset of premature aging phenotypes.

Dr. Chang is currently focusing on how dysfunctional telomeres activate the DNA damage pathway, and the mechanisms that repair them.He continues to use novel molecular and biochemical approaches, as well as the generation of new mouse models of telomere dysfunction, to address thesequestions.

Coauthors

Research Interests

DNA Damage; Molecular Biology; Pathology; Werner Syndrome; Telomere-Binding Proteins; Early Detection of Cancer; Diseases

Research Image

massive chromosome fusions after removal of the telomere binding protein TRF2

Selected Publications

  • Shelterin and the replisome: at the intersection of telomere repair and replication.Cicconi A, Chang S. Shelterin and the replisome: at the intersection of telomere repair and replication. Current Opinion In Genetics & Development 2020, 60: 77-84. PMID: 32171974, DOI: 10.1016/j.gde.2020.02.016.
  • WRN helicase is a synthetic lethal target in microsatellite unstable cancers.Chan EM, Shibue T, McFarland JM, Gaeta B, Ghandi M, Dumont N, Gonzalez A, McPartlan JS, Li T, Zhang Y, Bin Liu J, Lazaro JB, Gu P, Piett CG, Apffel A, Ali SO, Deasy R, Keskula P, Ng RWS, Roberts EA, Reznichenko E, Leung L, Alimova M, Schenone M, Islam M, Maruvka YE, Liu Y, Roper J, Raghavan S, Giannakis M, Tseng YY, Nagel ZD, D'Andrea A, Root DE, Boehm JS, Getz G, Chang S, Golub TR, Tsherniak A, Vazquez F, Bass AJ. WRN helicase is a synthetic lethal target in microsatellite unstable cancers. Nature 2019, 568: 551-556. PMID: 30971823, PMCID: PMC6580861, DOI: 10.1038/s41586-019-1102-x.
  • The Replisome Mediates A-NHEJ Repair of Telomeres Lacking POT1-TPP1 Independently of MRN Function.Rai R, Gu P, Broton C, Kumar-Sinha C, Chen Y, Chang S. The Replisome Mediates A-NHEJ Repair of Telomeres Lacking POT1-TPP1 Independently of MRN Function. Cell Reports 2019, 29: 3708-3725.e5. PMID: 31825846, PMCID: PMC7001145, DOI: 10.1016/j.celrep.2019.11.012.
  • CTC1-STN1 coordinates G- and C-strand synthesis to regulate telomere length.Gu P, Jia S, Takasugi T, Smith E, Nandakumar J, Hendrickson E, Chang S. CTC1-STN1 coordinates G- and C-strand synthesis to regulate telomere length. Aging Cell 2018, 17: e12783. PMID: 29774655, PMCID: PMC6052479, DOI: 10.1111/acel.12783.
  • Cytogenetic Analysis of Telomere Dysfunction.Rai R, Multani AS, Chang S. Cytogenetic Analysis of Telomere Dysfunction. Methods In Molecular Biology (Clifton, N.J.) 2017, 1587: 127-131. PMID: 28324504, DOI: 10.1007/978-1-4939-6892-3_12.
  • NBS1 Phosphorylation Status Dictates Repair Choice of Dysfunctional Telomeres.Rai R, Hu C, Broton C, Chen Y, Lei M, Chang S. NBS1 Phosphorylation Status Dictates Repair Choice of Dysfunctional Telomeres. Molecular Cell 2017, 65: 801-817.e4. PMID: 28216226, PMCID: PMC5639704, DOI: 10.1016/j.molcel.2017.01.016.
  • Probing the Telomere Damage Response.Rai R, Chang S. Probing the Telomere Damage Response. Methods In Molecular Biology (Clifton, N.J.) 2017, 1587: 133-138. PMID: 28324505, DOI: 10.1007/978-1-4939-6892-3_13.
  • Structural and functional analyses of the mammalian TIN2-TPP1-TRF2 telomeric complex.Hu C, Rai R, Huang C, Broton C, Long J, Xu Y, Xue J, Lei M, Chang S, Chen Y. Structural and functional analyses of the mammalian TIN2-TPP1-TRF2 telomeric complex. Cell Research 2017, 27: 1485-1502. PMID: 29160297, PMCID: PMC5717407, DOI: 10.1038/cr.2017.144.
  • Structural insights into POT1-TPP1 interaction and POT1 C-terminal mutations in human cancer.Chen C, Gu P, Wu J, Chen X, Niu S, Sun H, Wu L, Li N, Peng J, Shi S, Fan C, Huang M, Wong CC, Gong Q, Kumar-Sinha C, Zhang R, Pusztai L, Rai R, Chang S, Lei M. Structural insights into POT1-TPP1 interaction and POT1 C-terminal mutations in human cancer. Nature Communications 2017, 8: 14929. PMID: 28393832, PMCID: PMC5394241, DOI: 10.1038/ncomms14929.
  • Pot1 OB-fold mutations unleash telomere instability to initiate tumorigenesis.Gu P, Wang Y, Bisht KK, Wu L, Kukova L, Smith EM, Xiao Y, Bailey SM, Lei M, Nandakumar J, Chang S. Pot1 OB-fold mutations unleash telomere instability to initiate tumorigenesis. Oncogene 2017, 36: 1939-1951. PMID: 27869160, PMCID: PMC5383532, DOI: 10.1038/onc.2016.405.
  • Dysfunctional telomeres induce p53-dependent and independent apoptosis to compromise cellular proliferation and inhibit tumor formation.Wang Y, Wang X, Flores ER, Yu J, Chang S. Dysfunctional telomeres induce p53-dependent and independent apoptosis to compromise cellular proliferation and inhibit tumor formation. Aging Cell 2016, 15: 646-60. PMID: 27113195, PMCID: PMC4933665, DOI: 10.1111/acel.12476.
  • TRF2-RAP1 is required to protect telomeres from engaging in homologous recombination-mediated deletions and fusions.Rai R, Chen Y, Lei M, Chang S. TRF2-RAP1 is required to protect telomeres from engaging in homologous recombination-mediated deletions and fusions. Nature Communications 2016, 7: 10881. PMID: 26941064, PMCID: PMC4785230, DOI: 10.1038/ncomms10881.
  • Monitoring the DNA Damage Response at Dysfunctional Telomeres.Rai R, Chang S. Monitoring the DNA Damage Response at Dysfunctional Telomeres. Methods In Molecular Biology (Clifton, N.J.) 2015, 1343: 175-80. PMID: 26420717, DOI: 10.1007/978-1-4939-2963-4_14.
  • Synergistic tumor suppression by combined inhibition of telomerase and CDKN1A.Gupta R, Dong Y, Solomon PD, Wettersten HI, Cheng CJ, Min JN, Henson J, Dogra SK, Hwang SH, Hammock BD, Zhu LJ, Reddel RR, Saltzman WM, Weiss RH, Chang S, Green MR, Wajapeyee N. Synergistic tumor suppression by combined inhibition of telomerase and CDKN1A. Proceedings Of The National Academy Of Sciences Of The United States Of America 2014, 111: E3062-71. PMID: 25024194, PMCID: PMC4121806, DOI: 10.1073/pnas.1411370111.
  • Pot1a prevents telomere dysfunction and ATM-dependent neuronal loss.Lee Y, Brown EJ, Chang S, McKinnon PJ. Pot1a prevents telomere dysfunction and ATM-dependent neuronal loss. The Journal Of Neuroscience : The Official Journal Of The Society For Neuroscience 2014, 34: 7836-44. PMID: 24899707, PMCID: PMC4044246, DOI: 10.1523/JNEUROSCI.4245-13.2014.
  • The mINO80 chromatin remodeling complex is required for efficient telomere replication and maintenance of genome stability.Min JN, Tian Y, Xiao Y, Wu L, Li L, Chang S. The mINO80 chromatin remodeling complex is required for efficient telomere replication and maintenance of genome stability. Cell Research 2013, 23: 1396-413. PMID: 23979016, PMCID: PMC3847565, DOI: 10.1038/cr.2013.113.
  • Cooperation between p53 and the telomere-protecting shelterin component Pot1a in endometrial carcinogenesis.Akbay EA, Peña CG, Ruder D, Michel JA, Nakada Y, Pathak S, Multani AS, Chang S, Castrillon DH. Cooperation between p53 and the telomere-protecting shelterin component Pot1a in endometrial carcinogenesis. Oncogene 2013, 32: 2211-9. PMID: 22689059, PMCID: PMC3636499, DOI: 10.1038/onc.2012.232.
  • p16(INK4a) protects against dysfunctional telomere-induced ATR-dependent DNA damage responses.Wang Y, Sharpless N, Chang S. p16(INK4a) protects against dysfunctional telomere-induced ATR-dependent DNA damage responses. The Journal Of Clinical Investigation 2013, 123: 4489-501. PMID: 24091330, PMCID: PMC3784543, DOI: 10.1172/JCI69574.
  • Functional characterization of human CTC1 mutations reveals novel mechanisms responsible for the pathogenesis of the telomere disease Coats plus.Gu P, Chang S. Functional characterization of human CTC1 mutations reveals novel mechanisms responsible for the pathogenesis of the telomere disease Coats plus. Aging Cell 2013, 12: 1100-9. PMID: 23869908, PMCID: PMC4083614, DOI: 10.1111/acel.12139.
  • SLX4 assembles a telomere maintenance toolkit by bridging multiple endonucleases with telomeres.Wan B, Yin J, Horvath K, Sarkar J, Chen Y, Wu J, Wan K, Lu J, Gu P, Yu EY, Lue NF, Chang S, Liu Y, Lei M. SLX4 assembles a telomere maintenance toolkit by bridging multiple endonucleases with telomeres. Cell Reports 2013, 4: 861-9. PMID: 24012755, PMCID: PMC4334113, DOI: 10.1016/j.celrep.2013.08.017.
  • Single strand DNA binding proteins 1 and 2 protect newly replicated telomeres.Gu P, Deng W, Lei M, Chang S. Single strand DNA binding proteins 1 and 2 protect newly replicated telomeres. Cell Research 2013, 23: 705-19. PMID: 23459151, PMCID: PMC3641597, DOI: 10.1038/cr.2013.31.
  • Cancer chromosomes going to POT1.Chang S. Cancer chromosomes going to POT1. Nature Genetics 2013, 45: 473-5. PMID: 23619786, PMCID: PMC4040961, DOI: 10.1038/ng.2617.
  • RPA and POT1: friends or foes at telomeres?Flynn RL, Chang S, Zou L. RPA and POT1: friends or foes at telomeres? Cell Cycle (Georgetown, Tex.) 2012, 11: 652-7. PMID: 22373525, PMCID: PMC3318101, DOI: 10.4161/cc.11.4.19061.
  • CTC1 deletion results in defective telomere replication, leading to catastrophic telomere loss and stem cell exhaustion.Gu P, Min JN, Wang Y, Huang C, Peng T, Chai W, Chang S. CTC1 deletion results in defective telomere replication, leading to catastrophic telomere loss and stem cell exhaustion. The EMBO Journal 2012, 31: 2309-21. PMID: 22531781, PMCID: PMC3364752, DOI: 10.1038/emboj.2012.96.
  • Chromosome ends teach unexpected lessons on DNA damage signalling.Chang S. Chromosome ends teach unexpected lessons on DNA damage signalling. The EMBO Journal 2012, 31: 3380-1. PMID: 22842787, PMCID: PMC3419931, DOI: 10.1038/emboj.2012.199.
  • The RAG2 C terminus suppresses genomic instability and lymphomagenesis.Deriano L, Chaumeil J, Coussens M, Multani A, Chou Y, Alekseyenko AV, Chang S, Skok JA, Roth DB. The RAG2 C terminus suppresses genomic instability and lymphomagenesis. Nature 2011, 471: 119-23. PMID: 21368836, PMCID: PMC3174233, DOI: 10.1038/nature09755.
  • Probing the telomere damage response.Rai R, Chang S. Probing the telomere damage response. Methods In Molecular Biology (Clifton, N.J.) 2011, 735: 145-50. PMID: 21461819, PMCID: PMC3690558, DOI: 10.1007/978-1-61779-092-8_14.
  • TERRA and hnRNPA1 orchestrate an RPA-to-POT1 switch on telomeric single-stranded DNA.Flynn RL, Centore RC, O'Sullivan RJ, Rai R, Tse A, Songyang Z, Chang S, Karlseder J, Zou L. TERRA and hnRNPA1 orchestrate an RPA-to-POT1 switch on telomeric single-stranded DNA. Nature 2011, 471: 532-6. PMID: 21399625, PMCID: PMC3078637, DOI: 10.1038/nature09772.
  • A conserved motif within RAP1 has diversified roles in telomere protection and regulation in different organisms.Chen Y, Rai R, Zhou ZR, Kanoh J, Ribeyre C, Yang Y, Zheng H, Damay P, Wang F, Tsujii H, Hiraoka Y, Shore D, Hu HY, Chang S, Lei M. A conserved motif within RAP1 has diversified roles in telomere protection and regulation in different organisms. Nature Structural & Molecular Biology 2011, 18: 213-21. PMID: 21217703, PMCID: PMC3688267, DOI: 10.1038/nsmb.1974.
  • The E3 ubiquitin ligase Rnf8 stabilizes Tpp1 to promote telomere end protection.Rai R, Li JM, Zheng H, Lok GT, Deng Y, Huen MS, Chen J, Jin J, Chang S. The E3 ubiquitin ligase Rnf8 stabilizes Tpp1 to promote telomere end protection. Nature Structural & Molecular Biology 2011, 18: 1400-7. PMID: 22101936, PMCID: PMC3657743, DOI: 10.1038/nsmb.2172.
  • Essential roles for Pot1b in HSC self-renewal and survival.Wang Y, Shen MF, Chang S. Essential roles for Pot1b in HSC self-renewal and survival. Blood 2011, 118: 6068-77. PMID: 21948176, PMCID: PMC3234665, DOI: 10.1182/blood-2011-06-361527.
  • Defending the end zone: studying the players involved in protecting chromosome ends.Chan SS, Chang S. Defending the end zone: studying the players involved in protecting chromosome ends. FEBS Letters 2010, 584: 3773-8. PMID: 20579983, PMCID: PMC3657741, DOI: 10.1016/j.febslet.2010.06.016.
  • The telomere protein tankyrase 1 regulates DNA damage responses at telomeres.Chang S. The telomere protein tankyrase 1 regulates DNA damage responses at telomeres. Aging 2010, 2: 639-42. PMID: 21076181, PMCID: PMC2993793, DOI: 10.18632/aging.100221.
  • SNMIB/Apollo protects leading-strand telomeres against NHEJ-mediated repair.Lam YC, Akhter S, Gu P, Ye J, Poulet A, Giraud-Panis MJ, Bailey SM, Gilson E, Legerski RJ, Chang S. SNMIB/Apollo protects leading-strand telomeres against NHEJ-mediated repair. The EMBO Journal 2010, 29: 2230-41. PMID: 20551906, PMCID: PMC2905253, DOI: 10.1038/emboj.2010.58.
  • The function of classical and alternative non-homologous end-joining pathways in the fusion of dysfunctional telomeres.Rai R, Zheng H, He H, Luo Y, Multani A, Carpenter PB, Chang S. The function of classical and alternative non-homologous end-joining pathways in the fusion of dysfunctional telomeres. The EMBO Journal 2010, 29: 2598-610. PMID: 20588252, PMCID: PMC2928694, DOI: 10.1038/emboj.2010.142.
  • The telomeric protein SNM1B/Apollo is required for normal cell proliferation and embryonic development.Akhter S, Lam YC, Chang S, Legerski RJ. The telomeric protein SNM1B/Apollo is required for normal cell proliferation and embryonic development. Aging Cell 2010, 9: 1047-56. PMID: 20854421, PMCID: PMC3719988, DOI: 10.1111/j.1474-9726.2010.00631.x.
  • Gcn5 and SAGA regulate shelterin protein turnover and telomere maintenance.Atanassov BS, Evrard YA, Multani AS, Zhang Z, Tora L, Devys D, Chang S, Dent SY. Gcn5 and SAGA regulate shelterin protein turnover and telomere maintenance. Molecular Cell 2009, 35: 352-64. PMID: 19683498, PMCID: PMC2749492, DOI: 10.1016/j.molcel.2009.06.015.
  • Pot1b deletion and telomerase haploinsufficiency in mice initiate an ATR-dependent DNA damage response and elicit phenotypes resembling dyskeratosis congenita.He H, Wang Y, Guo X, Ramchandani S, Ma J, Shen MF, Garcia DA, Deng Y, Multani AS, You MJ, Chang S. Pot1b deletion and telomerase haploinsufficiency in mice initiate an ATR-dependent DNA damage response and elicit phenotypes resembling dyskeratosis congenita. Molecular And Cellular Biology 2009, 29: 229-40. PMID: 18936156, PMCID: PMC2612488, DOI: 10.1128/MCB.01400-08.
  • Multiple roles for MRE11 at uncapped telomeres.Deng Y, Guo X, Ferguson DO, Chang S. Multiple roles for MRE11 at uncapped telomeres. Nature 2009, 460: 914-8. PMID: 19633651, PMCID: PMC2760383, DOI: 10.1038/nature08196.
  • Dual roles of telomere dysfunction in initiation and suppression of tumorigenesis.Cosme-Blanco W, Chang S. Dual roles of telomere dysfunction in initiation and suppression of tumorigenesis. Experimental Cell Research 2008, 314: 1973-9. PMID: 18448098, PMCID: PMC3690559, DOI: 10.1016/j.yexcr.2008.03.011.
  • Critical and distinct roles of p16 and telomerase in regulating the proliferative life span of normal human prostate epithelial progenitor cells.Bhatia B, Jiang M, Suraneni M, Patrawala L, Badeaux M, Schneider-Broussard R, Multani AS, Jeter CR, Calhoun-Davis T, Hu L, Hu J, Tsavachidis S, Zhang W, Chang S, Hayward SW, Tang DG. Critical and distinct roles of p16 and telomerase in regulating the proliferative life span of normal human prostate epithelial progenitor cells. The Journal Of Biological Chemistry 2008, 283: 27957-27972. PMID: 18662989, PMCID: PMC2562067, DOI: 10.1074/jbc.M803467200.
  • Control of chromosome stability by the beta-TrCP-REST-Mad2 axis.Guardavaccaro D, Frescas D, Dorrello NV, Peschiaroli A, Multani AS, Cardozo T, Lasorella A, Iavarone A, Chang S, Hernando E, Pagano M. Control of chromosome stability by the beta-TrCP-REST-Mad2 axis. Nature 2008, 452: 365-9. PMID: 18354482, PMCID: PMC2707768, DOI: 10.1038/nature06641.
  • Telomere dysfunction and tumour suppression: the senescence connection.Deng Y, Chan SS, Chang S. Telomere dysfunction and tumour suppression: the senescence connection. Nature Reviews. Cancer 2008, 8: 450-8. PMID: 18500246, PMCID: PMC3688269, DOI: 10.1038/nrc2393.
  • Mre11 nuclease activity has essential roles in DNA repair and genomic stability distinct from ATM activation.Buis J, Wu Y, Deng Y, Leddon J, Westfield G, Eckersdorff M, Sekiguchi JM, Chang S, Ferguson DO. Mre11 nuclease activity has essential roles in DNA repair and genomic stability distinct from ATM activation. Cell 2008, 135: 85-96. PMID: 18854157, PMCID: PMC2645868, DOI: 10.1016/j.cell.2008.08.015.
  • Evidence that senescent human prostate epithelial cells enhance tumorigenicity: cell fusion as a potential mechanism and inhibition by p16INK4a and hTERT.Bhatia B, Multani AS, Patrawala L, Chen X, Calhoun-Davis T, Zhou J, Schroeder L, Schneider-Broussard R, Shen J, Pathak S, Chang S, Tang DG. Evidence that senescent human prostate epithelial cells enhance tumorigenicity: cell fusion as a potential mechanism and inhibition by p16INK4a and hTERT. International Journal Of Cancer. Journal International Du Cancer 2008, 122: 1483-95. PMID: 18059027, DOI: 10.1002/ijc.23222.
  • Dysfunctional telomeres activate an ATM-ATR-dependent DNA damage response to suppress tumorigenesis.Guo X, Deng Y, Lin Y, Cosme-Blanco W, Chan S, He H, Yuan G, Brown EJ, Chang S. Dysfunctional telomeres activate an ATM-ATR-dependent DNA damage response to suppress tumorigenesis. The EMBO Journal 2007, 26: 4709-19. PMID: 17948054, PMCID: PMC2080807, DOI: 10.1038/sj.emboj.7601893.
  • Overexpression of the low molecular weight cyclin E in transgenic mice induces metastatic mammary carcinomas through the disruption of the ARF-p53 pathway.Akli S, Van Pelt CS, Bui T, Multani AS, Chang S, Johnson D, Tucker S, Keyomarsi K. Overexpression of the low molecular weight cyclin E in transgenic mice induces metastatic mammary carcinomas through the disruption of the ARF-p53 pathway. Cancer Research 2007, 67: 7212-22. PMID: 17671189, DOI: 10.1158/0008-5472.CAN-07-0599.
  • Telomere dysfunction suppresses spontaneous tumorigenesis in vivo by initiating p53-dependent cellular senescence.Cosme-Blanco W, Shen MF, Lazar AJ, Pathak S, Lozano G, Multani AS, Chang S. Telomere dysfunction suppresses spontaneous tumorigenesis in vivo by initiating p53-dependent cellular senescence. EMBO Reports 2007, 8: 497-503. PMID: 17396137, PMCID: PMC1866197, DOI: 10.1038/sj.embor.7400937.
  • Role of telomeres and telomerase in genomic instability, senescence and cancer.Deng Y, Chang S. Role of telomeres and telomerase in genomic instability, senescence and cancer. Laboratory Investigation; A Journal Of Technical Methods And Pathology 2007, 87: 1071-6. PMID: 17767195, DOI: 10.1038/labinvest.3700673.
  • WRN at telomeres: implications for aging and cancer.Multani AS, Chang S. WRN at telomeres: implications for aging and cancer. Journal Of Cell Science 2007, 120: 713-21. PMID: 17314245, DOI: 10.1242/jcs.03397.
  • Pot1 deficiency initiates DNA damage checkpoint activation and aberrant homologous recombination at telomeres.Wu L, Multani AS, He H, Cosme-Blanco W, Deng Y, Deng JM, Bachilo O, Pathak S, Tahara H, Bailey SM, Deng Y, Behringer RR, Chang S. Pot1 deficiency initiates DNA damage checkpoint activation and aberrant homologous recombination at telomeres. Cell 2006, 126: 49-62. PMID: 16839876, DOI: 10.1016/j.cell.2006.05.037.
  • POT1b protects telomeres from end-to-end chromosomal fusions and aberrant homologous recombination.He H, Multani AS, Cosme-Blanco W, Tahara H, Ma J, Pathak S, Deng Y, Chang S. POT1b protects telomeres from end-to-end chromosomal fusions and aberrant homologous recombination. The EMBO Journal 2006, 25: 5180-90. PMID: 17053789, PMCID: PMC1630418, DOI: 10.1038/sj.emboj.7601294.
  • Block of T cell development in P53-deficient mice accelerates development of lymphomas with characteristic RAG-dependent cytogenetic alterations.Haines BB, Ryu CJ, Chang S, Protopopov A, Luch A, Kang YH, Draganov DD, Fragoso MF, Paik SG, Hong HJ, DePinho RA, Chen J. Block of T cell development in P53-deficient mice accelerates development of lymphomas with characteristic RAG-dependent cytogenetic alterations. Cancer Cell 2006, 9: 109-20. PMID: 16473278, DOI: 10.1016/j.ccr.2006.01.004.
  • Elevated telomere-telomere recombination in WRN-deficient, telomere dysfunctional cells promotes escape from senescence and engagement of the ALT pathway.Laud PR, Multani AS, Bailey SM, Wu L, Ma J, Kingsley C, Lebel M, Pathak S, DePinho RA, Chang S. Elevated telomere-telomere recombination in WRN-deficient, telomere dysfunctional cells promotes escape from senescence and engagement of the ALT pathway. Genes & Development 2005, 19: 2560-70. PMID: 16264192, PMCID: PMC1276730, DOI: 10.1101/gad.1321305.
  • A mouse model of Werner Syndrome: what can it tell us about aging and cancer?Chang S. A mouse model of Werner Syndrome: what can it tell us about aging and cancer? The International Journal Of Biochemistry & Cell Biology 2005, 37: 991-9. PMID: 15743673, DOI: 10.1016/j.biocel.2004.11.007.
  • Trp53R172H and KrasG12D cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice.Hingorani SR, Wang L, Multani AS, Combs C, Deramaudt TB, Hruban RH, Rustgi AK, Chang S, Tuveson DA. Trp53R172H and KrasG12D cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice. Cancer Cell 2005, 7: 469-83. PMID: 15894267, DOI: 10.1016/j.ccr.2005.04.023.
  • Modeling aging and cancer in the telomerase knockout mouse.Chang S. Modeling aging and cancer in the telomerase knockout mouse. Mutation Research 2005, 576: 39-53. PMID: 15927211, DOI: 10.1016/j.mrfmmm.2004.08.020.
  • Modeling premature aging syndromes with the telomerase knockout mouse.Chang S. Modeling premature aging syndromes with the telomerase knockout mouse. Current Molecular Medicine 2005, 5: 153-8. PMID: 15974868, DOI: 10.2174/1566524053586662.
  • Tumor-specific low molecular weight forms of cyclin E induce genomic instability and resistance to p21, p27, and antiestrogens in breast cancer.Akli S, Zheng PJ, Multani AS, Wingate HF, Pathak S, Zhang N, Tucker SL, Chang S, Keyomarsi K. Tumor-specific low molecular weight forms of cyclin E induce genomic instability and resistance to p21, p27, and antiestrogens in breast cancer. Cancer Research 2004, 64: 3198-208. PMID: 15126360, DOI: 10.1158/0008-5472.can-03-3672.
  • Essential role of limiting telomeres in the pathogenesis of Werner syndrome.Chang S, Multani AS, Cabrera NG, Naylor ML, Laud P, Lombard D, Pathak S, Guarente L, DePinho RA. Essential role of limiting telomeres in the pathogenesis of Werner syndrome. Nature Genetics 2004, 36: 877-82. PMID: 15235603, DOI: 10.1038/ng1389.
  • Mutations in the mineralocorticoid receptor gene cause autosomal dominant pseudohypoaldosteronism type I.Geller DS, Rodriguez-Soriano J, Vallo Boado A, Schifter S, Bayer M, Chang SS, Lifton RP. Mutations in the mineralocorticoid receptor gene cause autosomal dominant pseudohypoaldosteronism type I. Nature Genetics 1998, 19: 279-81. PMID: 9662404, DOI: 10.1038/966.
  • SLACS retrotransposon from Trypanosoma brucei gambiense is similar to mammalian LINEs.Aksoy S, Williams S, Chang S, Richards FF. SLACS retrotransposon from Trypanosoma brucei gambiense is similar to mammalian LINEs. Nucleic Acids Research 1990, 18: 785-92. PMID: 2156231, PMCID: PMC330328, DOI: 10.1093/nar/18.4.785.
  • Microcephalin 1/BRIT1-TRF2 interaction promotes telomere replication and repair, linking telomere dysfunction to primary microcephaly.Cicconi A, Rai R, Xiong X, Broton C, Al-Hiyasat A, Hu C, Dong S, Sun W, Garbarino J, Bindra RS, Schildkraut C, Chen Y, Chang S. Microcephalin 1/BRIT1-TRF2 interaction promotes telomere replication and repair, linking telomere dysfunction to primary microcephaly. Nature Communications 2020, 11: 5861. PMID: 33203878, PMCID: PMC7672075, DOI: 10.1038/s41467-020-19674-0.
  • Distinct functions of POT1 proteins contribute to the regulation of telomerase recruitment to telomeres.Gu P, Jia S, Takasugi T, Tesmer VM, Nandakumar J, Chen Y, Chang S. Distinct functions of POT1 proteins contribute to the regulation of telomerase recruitment to telomeres. Nature Communications 2021, 12: 5514. PMID: 34535663, PMCID: PMC8448735, DOI: 10.1038/s41467-021-25799-7.
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