Sandy Chang PhD, MD

Associate Professor of Laboratory Medicine and of Pathology; Associate Director, Molecular Diagnostics Laboratory

Research Interests

Mouse models of cancer; DNA damage; Telomere biology

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 thegeneration of new mouse models of telomere dysfunction, to address thesequestions.

Selected Publications

  • Chang S. 2013. Cancer chromosomes going to POT1. Nat Genet. 45(5):473-475.
  • 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.
  • Chang S. 2012. Chromosome ends teach unexpected lessons on DNA damage signalling. EMBO J. 31:3380-3381.
  • 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.
  • 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.
  • Wang Y, Shen MF, Chang S. 2011. Essential roles for Pot1b in hematopoietic stem cell self-renewal and survival. Blood 118(23):6068-6077.
  • 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.
  • 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.
  • 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#, Ming Lei M# . 2011. A conserved motif within RAP1 plays diversified roles in telomere protection and regulation in different organisms. Nature Structural and Molecular Biology. 18(2):213-221. #Co-corresponding authors
  • 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.


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