DNA Damage; Molecular Biology; Pathology; Werner Syndrome; Telomere-Binding Proteins
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 thegeneration of new mouse models of telomere dysfunction, to address thesequestions.
Cancer chromosomes going to POT1
Chang S. 2013. Cancer chromosomes going to POT1. Nat Genet. 45(5):473-475.
Single strand binding proteins 1 and 2 protect newly replicated telomeres
Gu P, Deng W, Lei M, and Chang S. 2013. Single strand binding proteins 1 and 2 protect newly replicated telomeres. Cell Research 23(5):705-719. See accompanying review "Mouse models uncap novel roles of SSBs" Bain AL, Shi W, Khanna KK. 2013 Cell Res. 2013 Jun;23(6):744-5.
Chromosome ends teach unexpected lessons on DNA damage signalling
Chang S. 2012. Chromosome ends teach unexpected lessons on DNA damage signalling. EMBO J. 31:3380-3381.
Cooperation between p53 and the telomere-protecting shelter in component Pot1a in endometrial carcinogenesis
Akbay EA, Peña CG, Ruder D, Michel JA, Nakada Y, Pathak S, Multani AS, Chang S, Castrillon DH. 2012. Cooperation between p53 and the telomere-protecting shelter in component Pot1a in endometrial carcinogenesis. Oncogene 32(17):2211-2219.
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. 2012. CTC1 deletion results in defective telomere replication, leading to catastrophic telomere loss and stem cell exhaustion. EMBO J. 31(10):2309-23021.
Essential roles for Pot1b in hematopoietic stem cell self-renewal and survival
Wang Y, Shen MF, Chang S. 2011. Essential roles for Pot1b in hematopoietic stem cell self-renewal and survival. Blood 118(23):6068-6077.
The E3 ubiquitin ligase RNF8 stabilizes TPP1 to promote telomere end protection
Rai R, Li JM, Zheng H, Lok G, Deng Y, Huen M, Chen J, Jin J and Chang S. 2011. The E3 ubiquitin ligase RNF8 stabilizes TPP1 to promote telomere end protection. Nature Structural and Molecular Biology 18(12):1400-1407.
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, and Zou L. 2011. TERRA and hnRNPA1 orchestrate an RPA-to-POT1 switch on telomeric single-stranded DNA. Nature. 471(7339):532-536.
A conserved motif within RAP1 plays diversified roles in telomere protection and regulation in different organisms.
Chen Y, Rai R, Zhou ZR, Kanoh J, Ribeyre C, et al . 2011. A conserved motif within RAP1 plays diversified roles in telomere protection and regulation in different organisms. Nature Structural and Molecular Biology 18: 213-221.
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. 2010. The function of classical and alternative non-homologous end-joining pathways in the fusion of dysfunctional telomeres. EMBO J. 29(15):2598-610.
SNMIB/Apollo generates 3’ single-stranded overhangs at leading-strand telomeres to protect against NHEJ-mediated repair
Lam YC, Akhter S, Gu P, Bailey SM, Legerski RJ and Chang S. 2010. SNMIB/Apollo generates 3’ single-stranded overhangs at leading-strand telomeres to protect against NHEJ-mediated repair. EMBO J. (2010) 29(13):2230-41.
Multiple roles for Mre11 at uncapped telomeres
Deng Y, Guo X, Ferguson DO and Chang S. 2009. Multiple roles for Mre11 at uncapped telomeres. Nature. 460 (7257):914-918.
ot1b 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 and Chang S. 2009. Pot1b deletion and telomerase haploinsufficiency in mice initiate an ATR-dependent DNA damage response and elicit phenotypes resembling Dyskeratosis Congenita. Mol Cell Biol. 29(1):229-240. PMCID: PMC2612488
An Unexpected Role for Gcn5 and SAGA in Shelterin Protein Turnover and Telomere Maintenance
Atanassov B, Evrard YA, Multani A, Zhang Z, Tora L, Devys D, Chang S and Dent S. 2009. An Unexpected Role for Gcn5 and SAGA in Shelterin Protein Turnover and Telomere Maintenance. Molecular Cell. 35(3) 352-364.
Telomere dysfunction and tumour suppression: the senescence connection
Deng Y, Chan SS, Chang S. 2008. Telomere dysfunction and tumour suppression: the senescence connection. Nat Rev Cancer 8:450-458.
Control of chromosome stability by the ?TRCP-REST-MAD2 axis
Guardavaccaro D, Frescas D, Dorrello NV, Peschiaroli A, Multani AS, Cardozo T, Lasorella A, Iavarone A, Chang S, Hernando E, and Pagano M. 2008. Control of chromosome stability by the ?TRCP-REST-MAD2 axis. Nature. 452: 365-369. PMCID: PMC2707768
Nuclease activity of Mre11 serves essential roles in DNA repair and genomic stability distinct from ATM activation
Buis J, Wu Y, Deng Y, Leddon J, Bryson A, Chang S and Ferguson D. 2008 Nuclease activity of Mre11 serves essential roles in DNA repair and genomic stability distinct from ATM activation. Cell 135:85-96. PMCID: PMC2645868
Telomere dysfunction suppresses spontaneous tumorigenesis in vivo by activating p53-mediated cellular senescence
Cosme-Blanco W, Shen MF, Lazar A, Pathak S, Lozano G, Multani AS, and Chang S. 2007. Telomere dysfunction suppresses spontaneous tumorigenesis in vivo by activating p53-mediated cellular senescence. EMBO Reports. 8(5):497-503.
Dysfunctional Telomeres Activate an ATM-ATR-Dependent DNA Damage Response to Suppress Tumorigenesis
Guo X, DengY, Lin Y, Cosme-Blanco W, Chan S, He H, Yuan G, Brown EJ and Chang S. 2007. Dysfunctional Telomeres Activate an ATM-ATR-Dependent DNA Damage Response to Suppress Tumorigenesis. EMBO J. 26:4709-4719.
Pot1 Deficiency Initiates DNA Damage Checkpoint Activation and Aberrant Homologous Recombination at Telomeres
Wu L, Multani AS, He H, Cosme-Blanco W, Deng Y, et al. 2006. Pot1 Deficiency Initiates DNA Damage Checkpoint Activation and Aberrant Homologous Recombination at Telomeres. Cell. 2006 Jul 14;126(1):49-62.
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, and Chang S. 2006. Pot1b Protects Telomeres From End-to-End Chromosomal Fusions and Aberrant Homologous Recombination. EMBO J. 25(21): 5180-5190.
Elevated Telomere-telomere Recombination Correlates with Increased Cellular Immortalization and Transformation in G5 mTerc-/- Wrn-/- Mouse Cells
Laud PA, Bailey SM, Multani AM, Kingsley C, Wu L, Pathak S, DePinho RA and Chang S. 2005. Elevated Telomere-telomere Recombination Correlates with Increased Cellular Immortalization and Transformation in G5 mTerc-/- Wrn-/- Mouse Cells. Genes and Development 19:2560-2570.
Full List of PubMed Publications
- 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 Aug; 2016 Apr 26. PMID: 27113195
- Rai R, Chen Y, Lei M, Chang S: TRF2-RAP1 is required to protect telomeres from engaging in homologous recombination-mediated deletions and fusions. Nat Commun. 2016 Mar 4; 2016 Mar 4. PMID: 26941064
- Rai R, Chang S: Monitoring the DNA Damage Response at Dysfunctional Telomeres. Methods Mol Biol. 2015. PMID: 26420717
- 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. Proc Natl Acad Sci U S A. 2014 Jul 29; 2014 Jul 14. PMID: 25024194
- Lee Y, Brown EJ, Chang S, McKinnon PJ: Pot1a prevents telomere dysfunction and ATM-dependent neuronal loss. J Neurosci. 2014 Jun 4. PMID: 24899707
- 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 Dec; 2013 Sep 4. PMID: 23869908
- 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 Res. 2013 Dec; 2013 Aug 27. PMID: 23979016
- Gu P, Deng W, Lei M, Chang S: Single strand DNA binding proteins 1 and 2 protect newly replicated telomeres. Cell Res. 2013 May; 2013 Mar 5. PMID: 23459151
- Chang S: Cancer chromosomes going to POT1. Nat Genet. 2013 May. PMID: 23619786
- Chang SS, Chen S, McAvay GJ, Tinetti ME: Effect of coexisting chronic obstructive pulmonary disease and cognitive impairment on health outcomes in older adults. J Am Geriatr Soc. 2012 Oct; 2012 Oct 4. PMID: 23035917
- Chang S: Chromosome ends teach unexpected lessons on DNA damage signalling. EMBO J. 2012 Aug 15; 2012 Jul 27. PMID: 22842787
- 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. EMBO J. 2012 May 16; 2012 Apr 24. PMID: 22531781
- Chang SS, Weiss CO, Xue QL, Fried LP: Association between inflammatory-related disease burden and frailty: results from the Women's Health and Aging Studies (WHAS) I and II. Arch Gerontol Geriatr. 2012 Jan-Feb; 2011 Jul 16. PMID: 21763008
- Wang Y, Shen MF, Chang S: Essential roles for Pot1b in HSC self-renewal and survival. Blood. 2011 Dec 1; 2011 Sep 23. PMID: 21948176
- 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. Nat Struct Mol Biol. 2011 Nov 20; 2011 Nov 20. PMID: 22101936
- Tinetti ME, McAvay G, Chang SS, Ning Y, Newman AB, Fitzpatrick A, Fried TR, Harris TB, Nevitt MC, Satterfield S, Yaffe K, Peduzzi P: Effect of chronic disease-related symptoms and impairments on universal health outcomes in older adults. J Am Geriatr Soc. 2011 Sep; 2011 Aug 24. PMID: 21883120
- Tinetti ME, McAvay GJ, Chang SS, Newman AB, Fitzpatrick AL, Fried TR, Peduzzi PN: Contribution of multiple chronic conditions to universal health outcomes. J Am Geriatr Soc. 2011 Sep; 2011 Aug 30. PMID: 21883118
- Chang SS, Vaz Fragoso CA, Van Ness PH, Fried LP, Tinetti ME: Association between combined interleukin-6 and C-reactive protein levels and pulmonary function in older women: results from the Women's Health and Aging Studies I and II. J Am Geriatr Soc. 2011 Jan. PMID: 21226682
- Chang SS, Weiss CO, Xue QL, Fried LP: Patterns of comorbid inflammatory diseases in frail older women: the Women's Health and Aging Studies I and II. J Gerontol A Biol Sci Med Sci. 2010 Apr; 2009 Nov 23. PMID: 19933749