Sandy Chang
Research & Publications
Biography
News
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
- Author Correction: Homology directed telomere clustering, ultrabright telomere formation and nuclear envelope rupture in cells lacking TRF2B and RAP1Rai R, Biju K, Sun W, Sodeinde T, Al-Hiyasat A, Morgan J, Ye X, Li X, Chen Y, Chang S. Author Correction: Homology directed telomere clustering, ultrabright telomere formation and nuclear envelope rupture in cells lacking TRF2B and RAP1 Nature Communications 2023, 14: 3319. PMID: 37286532, PMCID: PMC10247812, DOI: 10.1038/s41467-023-39144-7.
- Homology directed telomere clustering, ultrabright telomere formation and nuclear envelope rupture in cells lacking TRF2B and RAP1Rai R, Biju K, Sun W, Sodeinde T, Al-Hiyasat A, Morgan J, Ye X, Li X, Chen Y, Chang S. Homology directed telomere clustering, ultrabright telomere formation and nuclear envelope rupture in cells lacking TRF2B and RAP1 Nature Communications 2023, 14: 2144. PMID: 37059728, PMCID: PMC10104862, DOI: 10.1038/s41467-023-37761-w.
- Distinct functions of POT1 proteins contribute to the regulation of telomerase recruitment to telomeresGu 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.
- Microcephalin 1/BRIT1-TRF2 interaction promotes telomere replication and repair, linking telomere dysfunction to primary microcephalyCicconi 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.
- Shelterin and the replisome: at the intersection of telomere repair and replicationCicconi 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.
- The Replisome Mediates A-NHEJ Repair of Telomeres Lacking POT1-TPP1 Independently of MRN FunctionRai 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.
- WRN helicase is a synthetic lethal target in microsatellite unstable cancersChan 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.
- CTC1‐STN1 coordinates G‐ and C‐strand synthesis to regulate telomere lengthGu 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.
- Structural and functional analyses of the mammalian TIN2-TPP1-TRF2 telomeric complexHu 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 cancerChen 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.
- Cytogenetic Analysis of Telomere DysfunctionRai R, Multani AS, Chang S. Cytogenetic Analysis of Telomere Dysfunction 2017, 1587: 127-131. PMID: 28324504, DOI: 10.1007/978-1-4939-6892-3_12.
- Probing the Telomere Damage ResponseRai R, Chang S. Probing the Telomere Damage Response 2017, 1587: 133-138. PMID: 28324505, DOI: 10.1007/978-1-4939-6892-3_13.
- NBS1 Phosphorylation Status Dictates Repair Choice of Dysfunctional TelomeresRai 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.
- Pot1 OB-fold mutations unleash telomere instability to initiate tumorigenesisGu 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 2016, 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 formationWang 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: 646-660. PMID: 27113195, PMCID: PMC4933665, DOI: 10.1111/acel.12476.
- TRF2-RAP1 is required to protect telomeres from engaging in homologous recombination-mediated deletions and fusionsRai 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 TelomeresRai R, Chang S. Monitoring the DNA Damage Response at Dysfunctional Telomeres 2015, 1343: 175-180. PMID: 26420717, DOI: 10.1007/978-1-4939-2963-4_14.
- Synergistic tumor suppression by combined inhibition of telomerase and CDKN1AGupta 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-e3071. PMID: 25024194, PMCID: PMC4121806, DOI: 10.1073/pnas.1411370111.
- Pot1a Prevents Telomere Dysfunction and ATM-Dependent Neuronal LossLee Y, Brown EJ, Chang S, McKinnon PJ. Pot1a Prevents Telomere Dysfunction and ATM-Dependent Neuronal Loss Journal Of Neuroscience 2014, 34: 7836-7844. PMID: 24899707, PMCID: PMC4044246, DOI: 10.1523/jneurosci.4245-13.2014.
- p16INK4a protects against dysfunctional telomere–induced ATR-dependent DNA damage responsesWang Y, Sharpless N, Chang S. p16INK4a protects against dysfunctional telomere–induced ATR-dependent DNA damage responses Journal Of Clinical Investigation 2013, 123: 4489-4501. PMID: 24091330, PMCID: PMC3784543, DOI: 10.1172/jci69574.
- SLX4 Assembles a Telomere Maintenance Toolkit by Bridging Multiple Endonucleases with TelomeresWan 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: 861-869. PMID: 24012755, PMCID: PMC4334113, DOI: 10.1016/j.celrep.2013.08.017.
- Functional characterization of human CTC1 mutations reveals novel mechanisms responsible for the pathogenesis of the telomere disease Coats plusGu 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: 1100-1109. PMID: 23869908, PMCID: PMC4083614, DOI: 10.1111/acel.12139.
- The mINO80 chromatin remodeling complex is required for efficient telomere replication and maintenance of genome stabilityMin 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: 1396-1413. PMID: 23979016, PMCID: PMC3847565, DOI: 10.1038/cr.2013.113.
- Cancer chromosomes going to POT1Chang S. Cancer chromosomes going to POT1 Nature Genetics 2013, 45: 473-475. PMID: 23619786, PMCID: PMC4040961, DOI: 10.1038/ng.2617.
- Single strand DNA binding proteins 1 and 2 protect newly replicated telomeresGu P, Deng W, Lei M, Chang S. Single strand DNA binding proteins 1 and 2 protect newly replicated telomeres Cell Research 2013, 23: 705-719. PMID: 23459151, PMCID: PMC3641597, DOI: 10.1038/cr.2013.31.
- Chromosome ends teach unexpected lessons on DNA damage signallingChang S. Chromosome ends teach unexpected lessons on DNA damage signalling The EMBO Journal 2012, 31: 3380-3381. PMID: 22842787, PMCID: PMC3419931, DOI: 10.1038/emboj.2012.199.
- Cooperation between p53 and the telomere-protecting shelterin component Pot1a in endometrial carcinogenesisAkbay 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 2012, 32: 2211-2219. PMID: 22689059, PMCID: PMC3636499, DOI: 10.1038/onc.2012.232.
- CTC1 deletion results in defective telomere replication, leading to catastrophic telomere loss and stem cell exhaustionGu P, Min J, 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: 2309-2321. PMID: 22531781, PMCID: PMC3364752, DOI: 10.1038/emboj.2012.96.
- RPA and POT1Flynn RL, Chang S, Zou L. RPA and POT1 Cell Cycle 2012, 11: 652-657. PMID: 22373525, PMCID: PMC3318101, DOI: 10.4161/cc.11.4.19061.
- The E3 ubiquitin ligase Rnf8 stabilizes Tpp1 to promote telomere end protectionRai 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: 1400-1407. PMID: 22101936, PMCID: PMC3657743, DOI: 10.1038/nsmb.2172.
- Essential roles for Pot1b in HSC self-renewal and survivalWang Y, Shen MF, Chang S. Essential roles for Pot1b in HSC self-renewal and survival Blood 2011, 118: 6068-6077. PMID: 21948176, PMCID: PMC3234665, DOI: 10.1182/blood-2011-06-361527.
- TERRA and hnRNPA1 orchestrate an RPA-to-POT1 switch on telomeric single-stranded DNAFlynn RL, Centore RC, O’Sullivan R, 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: 532-536. PMID: 21399625, PMCID: PMC3078637, DOI: 10.1038/nature09772.
- Probing the Telomere Damage ResponseRai R, Chang S. Probing the Telomere Damage Response 2011, 735: 145-150. PMID: 21461819, PMCID: PMC3690558, DOI: 10.1007/978-1-61779-092-8_14.
- Cytogenetic Analysis of Telomere DysfunctionMultani A, Chang S. Cytogenetic Analysis of Telomere Dysfunction 2011, 735: 139-143. PMID: 21461818, PMCID: PMC3725757, DOI: 10.1007/978-1-61779-092-8_13.
- The RAG2 C terminus suppresses genomic instability and lymphomagenesisDeriano 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: 119-123. PMID: 21368836, PMCID: PMC3174233, DOI: 10.1038/nature09755.
- A conserved motif within RAP1 has diversified roles in telomere protection and regulation in different organismsChen 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: 213-221. PMID: 21217703, PMCID: PMC3688267, DOI: 10.1038/nsmb.1974.
- The telomeric protein SNM1B/Apollo is required for normal cell proliferation and embryonic developmentAkhter 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: 1047-1056. PMID: 20854421, PMCID: PMC3719988, DOI: 10.1111/j.1474-9726.2010.00631.x.
- The telomere protein tankyrase 1 regulates DNA damage responses at telomeresChang S. The telomere protein tankyrase 1 regulates DNA damage responses at telomeres Aging 2010, 2: 639-642. PMID: 21076181, PMCID: PMC2993793, DOI: 10.18632/aging.100221.
- The function of classical and alternative non‐homologous end‐joining pathways in the fusion of dysfunctional telomeresRai 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: 2598-2610. PMID: 20588252, PMCID: PMC2928694, DOI: 10.1038/emboj.2010.142.
- Defending the end zone: Studying the players involved in protecting chromosome endsChan SS, Chang S. Defending the end zone: Studying the players involved in protecting chromosome ends FEBS Letters 2010, 584: 3773-3778. PMID: 20579983, PMCID: PMC3657741, DOI: 10.1016/j.febslet.2010.06.016.
- SNMIB/Apollo protects leading‐strand telomeres against NHEJ‐mediated repairLam YC, Akhter S, Gu P, Ye J, Poulet A, Giraud‐Panis M, Bailey SM, Gilson E, Legerski RJ, Chang S. SNMIB/Apollo protects leading‐strand telomeres against NHEJ‐mediated repair The EMBO Journal 2010, 29: 2230-2241. PMID: 20551906, PMCID: PMC2905253, DOI: 10.1038/emboj.2010.58.
- Aurora Kinase A Promotes Ovarian Tumorigenesis through Dysregulation of the Cell Cycle and Suppression of BRCA2Yang G, Chang B, Yang F, Guo X, Cai K, Xiao X, Wang H, Sen S, Hung M, Mills G, Chang S, Multani A, Mercado-Uribe I, Liu J. Aurora Kinase A Promotes Ovarian Tumorigenesis through Dysregulation of the Cell Cycle and Suppression of BRCA2 Clinical Cancer Research 2010, 16: 3171-3181. PMID: 20423983, PMCID: PMC2930838, DOI: 10.1158/1078-0432.ccr-09-3171.
- BRIT1/MCPH1 Is Essential for Mitotic and Meiotic Recombination DNA Repair and Maintaining Genomic Stability in MiceLiang Y, Gao H, Lin S, Peng G, Huang X, Zhang P, Goss J, Brunicardi F, Multani A, Chang S, Li K. BRIT1/MCPH1 Is Essential for Mitotic and Meiotic Recombination DNA Repair and Maintaining Genomic Stability in Mice PLOS Genetics 2010, 6: e1000826. PMID: 20107607, PMCID: PMC2809772, DOI: 10.1371/journal.pgen.1000826.
- Replicative Senescence as an Intrinsic Tumor-Suppressor MechanismChang S. Replicative Senescence as an Intrinsic Tumor-Suppressor Mechanism 2009, 201-217. DOI: 10.1007/978-1-4419-1075-2_8.
- Gcn5 and SAGA Regulate Shelterin Protein Turnover and Telomere MaintenanceAtanassov 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: 352-364. PMID: 19683498, PMCID: PMC2749492, DOI: 10.1016/j.molcel.2009.06.015.
- Multiple roles for MRE11 at uncapped telomeresDeng Y, Guo X, Ferguson DO, Chang S. Multiple roles for MRE11 at uncapped telomeres Nature 2009, 460: 914-918. PMID: 19633651, PMCID: PMC2760383, DOI: 10.1038/nature08196.
- Pot1b Deletion and Telomerase Haploinsufficiency in Mice Initiate an ATR-Dependent DNA Damage Response and Elicit Phenotypes Resembling Dyskeratosis CongenitaHe 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: 229-240. PMID: 18936156, PMCID: PMC2612488, DOI: 10.1128/mcb.01400-08.
- Mre11 Nuclease Activity Has Essential Roles in DNA Repair and Genomic Stability Distinct from ATM ActivationBuis 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.
- 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* Journal Of Biological Chemistry 2008, 283: 27957-27972. PMID: 18662989, PMCID: PMC2562067, DOI: 10.1074/jbc.m803467200.
- Telomere dysfunction and tumour suppression: the senescence connectionDeng Y, Chan SS, Chang S. Telomere dysfunction and tumour suppression: the senescence connection Nature Reviews Cancer 2008, 8: 450-458. PMID: 18500246, PMCID: PMC3688269, DOI: 10.1038/nrc2393.
- Dual roles of telomere dysfunction in initiation and suppression of tumorigenesisCosme-Blanco W, Chang S. Dual roles of telomere dysfunction in initiation and suppression of tumorigenesis Experimental Cell Research 2008, 314: 1973-1979. PMID: 18448098, PMCID: PMC3690559, DOI: 10.1016/j.yexcr.2008.03.011.
- Control of chromosome stability by the β-TrCP–REST–Mad2 axisGuardavaccaro 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 β-TrCP–REST–Mad2 axis Nature 2008, 452: 365-369. PMID: 18354482, PMCID: PMC2707768, DOI: 10.1038/nature06641.
- Initiation of Genomic Instability, Cellular Senescence, and Organismal Aging by Dysfunctional TelomeresChang S. Initiation of Genomic Instability, Cellular Senescence, and Organismal Aging by Dysfunctional Telomeres 2008, 57-75. DOI: 10.1007/978-3-540-73709-4_4.
- Evidence that senescent human prostate epithelial cells enhance tumorigenicity: Cell fusion as a potential mechanism and inhibition by p16INK4a and hTERTBhatia 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 2007, 122: 1483-1495. PMID: 18059027, DOI: 10.1002/ijc.23222.
- Dysfunctional telomeres activate an ATM‐ATR‐dependent DNA damage response to suppress tumorigenesisGuo 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: 4709-4719. PMID: 17948054, PMCID: PMC2080807, DOI: 10.1038/sj.emboj.7601893.
- Role of telomeres and telomerase in genomic instability, senescence and cancerDeng Y, Chang S. Role of telomeres and telomerase in genomic instability, senescence and cancer Laboratory Investigation 2007, 87: 1071-1076. PMID: 17767195, DOI: 10.1038/labinvest.3700673.
- Overexpression of the Low Molecular Weight Cyclin E in Transgenic Mice Induces Metastatic Mammary Carcinomas through the Disruption of the ARF-p53 PathwayAkli 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: 7212-7222. PMID: 17671189, DOI: 10.1158/0008-5472.can-07-0599.
- Telomere dysfunction suppresses spontaneous tumorigenesis in vivo by initiating p53‐dependent cellular senescenceCosme-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.
- WRN at telomeres: implications for aging and cancerMultani AS, Chang S. WRN at telomeres: implications for aging and cancer Journal Of Cell Science 2007, 120: 713-721. PMID: 17314245, DOI: 10.1242/jcs.03397.
- POT1b protects telomeres from end‐to‐end chromosomal fusions and aberrant homologous recombinationHe 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: 5180-5190. PMID: 17053789, PMCID: PMC1630418, DOI: 10.1038/sj.emboj.7601294.
- Pot1 Deficiency Initiates DNA Damage Checkpoint Activation and Aberrant Homologous Recombination at TelomeresWu 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.
- GCN5 Functions in Telomere Maintenance and Neural DevelopmentDent S, Evrard Y, Lin W, Bu P, Phan H, Chang S, Multani A. GCN5 Functions in Telomere Maintenance and Neural Development The FASEB Journal 2006, 20: a1472-a1472. DOI: 10.1096/fasebj.20.5.a1472-e.
- Block of T cell development in P53-deficient mice accelerates development of lymphomas with characteristic RAG-dependent cytogenetic alterationsHaines 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: 109-120. 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 pathwayLaud 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: 2560-2570. PMID: 16264192, PMCID: PMC1276730, DOI: 10.1101/gad.1321305.
- Modeling aging and cancer in the telomerase knockout mouseChang S. Modeling aging and cancer in the telomerase knockout mouse Mutation Research/Fundamental And Molecular Mechanisms Of Mutagenesis 2005, 576: 39-53. PMID: 15927211, DOI: 10.1016/j.mrfmmm.2004.08.020.
- Trp53R172H and KrasG12D cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in miceHingorani 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: 469-483. PMID: 15894267, DOI: 10.1016/j.ccr.2005.04.023.
- Modeling premature aging syndromes with the telomerase knockout mouse.Chang S. Modeling premature aging syndromes with the telomerase knockout mouse. 2005, 5: 153-8. PMID: 15974868, DOI: 10.2174/1566524053586662.
- 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 2004, 37: 991-999. PMID: 15743673, DOI: 10.1016/j.biocel.2004.11.007.
- UV-Induced B-Cell Lymphomas in p53 Heterozygous Mice.Miyahara Y, Kazimi N, Multani A, Pathak S, Chang S, Angkasekwinai Y, Qin X, Ullrich S. UV-Induced B-Cell Lymphomas in p53 Heterozygous Mice. Blood 2004, 104: 1370-1370. DOI: 10.1182/blood.v104.11.1370.1370.
- Essential role of limiting telomeres in the pathogenesis of Werner syndromeChang 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: 877-882. PMID: 15235603, DOI: 10.1038/ng1389.
- Tumor-Specific Low Molecular Weight Forms of Cyclin E Induce Genomic Instability and Resistance to p21, p27, and Antiestrogens in Breast CancerAkli 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: 3198-3208. PMID: 15126360, DOI: 10.1158/0008-5472.can-03-3672.
- Endogenous oncogenic K-rasG12D stimulates proliferation and widespread neoplastic and developmental defectsTuveson D, Shaw A, Willis N, Silver D, Jackson E, Chang S, Mercer K, Grochow R, Hock H, Crowley D, Hingorani S, Zaks T, King C, Jacobetz M, Wang L, Bronson R, Orkin S, DePinho R, Jacks T. Endogenous oncogenic K-rasG12D stimulates proliferation and widespread neoplastic and developmental defects Cancer Cell 2004, 5: 375-387. PMID: 15093544, DOI: 10.1016/s1535-6108(04)00085-6.
- Chromosome stability, in the absence of apoptosis, is critical for suppression of tumorigenesis in Trp53 mutant miceLiu G, Parant J, Lang G, Chau P, Chavez-Reyes A, El-Naggar A, Multani A, Chang S, Lozano G. Chromosome stability, in the absence of apoptosis, is critical for suppression of tumorigenesis in Trp53 mutant mice Nature Genetics 2003, 36: 63-68. PMID: 14702042, DOI: 10.1038/ng1282.
- Telomere-based crisis: functional differences between telomerase activation and ALT in tumor progressionChang S, Khoo C, Naylor M, Maser R, DePinho R. Telomere-based crisis: functional differences between telomerase activation and ALT in tumor progression Genes & Development 2003, 17: 88-100. PMID: 12514102, PMCID: PMC195968, DOI: 10.1101/gad.1029903.
- Telomerase extracurricular activitiesChang S, DePinho R. Telomerase extracurricular activities Proceedings Of The National Academy Of Sciences Of The United States Of America 2002, 99: 12520-12522. PMID: 12271146, PMCID: PMC130491, DOI: 10.1073/pnas.212514699.
- Telomere dysfunction provokes regional amplification and deletion in cancer genomesO'Hagan R, Chang S, Maser R, Mohan R, Artandi S, Chin L, DePinho R. Telomere dysfunction provokes regional amplification and deletion in cancer genomes Cancer Cell 2002, 2: 149-155. PMID: 12204535, DOI: 10.1016/s1535-6108(02)00094-6.
- Rescue of a telomere length defect of Nijmegen breakage syndrome cells requires NBS and telomerase catalytic subunitRanganathan V, Heine W, Ciccone D, Rudolph K, Wu X, Chang S, Hai H, Ahearn I, Livingston D, Resnick I, Rosen F, Seemanova E, Jarolim P, DePinho R, Weaver D. Rescue of a telomere length defect of Nijmegen breakage syndrome cells requires NBS and telomerase catalytic subunit Current Biology 2001, 11: 962-966. PMID: 11448772, DOI: 10.1016/s0960-9822(01)00267-6.
- Modeling chromosomal instability and epithelial carcinogenesis in the telomerase-deficient mouseChang S, Khoo C, DePinho R. Modeling chromosomal instability and epithelial carcinogenesis in the telomerase-deficient mouse Seminars In Cancer Biology 2001, 11: 227-238. PMID: 11407947, DOI: 10.1006/scbi.2000.0374.
- Telomere dysfunction impairs DNA repair and enhances sensitivity to ionizing radiationWong K, Chang S, Weiler S, Ganesan S, Chaudhuri J, Zhu C, Artandi S, Rudolph K, Gottlieb G, Chin L, Alt F, DePinho R. Telomere dysfunction impairs DNA repair and enhances sensitivity to ionizing radiation Nature Genetics 2000, 26: 85-88. PMID: 10973255, DOI: 10.1038/79232.
- Telomere dysfunction promotes non-reciprocal translocations and epithelial cancers in miceArtandi S, Chang S, Lee S, Alson S, Gottlieb G, Chin L, DePinho R. Telomere dysfunction promotes non-reciprocal translocations and epithelial cancers in mice Nature 2000, 406: 641-645. PMID: 10949306, DOI: 10.1038/35020592.
- The nonhomologous end-joining pathway of DNA repair is required for genomic stability and the suppression of translocationsFerguson D, Sekiguchi J, Chang S, Frank K, Gao Y, DePinho R, Alt F. The nonhomologous end-joining pathway of DNA repair is required for genomic stability and the suppression of translocations Proceedings Of The National Academy Of Sciences Of The United States Of America 2000, 97: 6630-6633. PMID: 10823907, PMCID: PMC18682, DOI: 10.1073/pnas.110152897.
- Inhibition of Experimental Liver Cirrhosis in Mice by Telomerase Gene DeliveryRudolph K, Chang S, Millard M, Schreiber-Agus N, DePinho R. Inhibition of Experimental Liver Cirrhosis in Mice by Telomerase Gene Delivery Science 2000, 287: 1253-1258. PMID: 10678830, DOI: 10.1126/science.287.5456.1253.
- Longevity, Stress Response, and Cancer in Aging Telomerase-Deficient MiceRudolph K, Chang S, Lee H, Blasco M, Gottlieb G, Greider C, DePinho R. Longevity, Stress Response, and Cancer in Aging Telomerase-Deficient Mice Cell 1999, 96: 701-712. PMID: 10089885, DOI: 10.1016/s0092-8674(00)80580-2.
- Establishment of an in vitro cell model system to study human prostate carcinogenesis.Ozen M, Multani A, Chang S, Voneschenbach A, Chung L, Pathak S. Establishment of an in vitro cell model system to study human prostate carcinogenesis. International Journal Of Oncology 1996, 8: 883-8. PMID: 21544441, DOI: 10.3892/ijo.8.5.883.