Sandy Chang, MD, PhD, BS
Professor of Laboratory Medicine, of Pathology and of Molecular Biophysics and BiochemistryCards
Appointments
Additional Titles
Associate Director, Molecular Diagnostics Laboratory
Contact Info
Appointments
Additional Titles
Associate Director, Molecular Diagnostics Laboratory
Contact Info
Appointments
Additional Titles
Associate Director, Molecular Diagnostics Laboratory
Contact Info
About
Titles
Professor of Laboratory Medicine, of Pathology and of Molecular Biophysics and Biochemistry
Associate Director, Molecular Diagnostics LaboratoryBiography
Dr. Chang graduated with a BS from Yale College in 1988, and obtained his MD from Cornell University Medical College and his PhD from Rockefeller University in 1997. He completed residency in Clinical Pathology at the Brigham and Women's Hospital, and did his postdoctoral fellowship with Dr. Ronald DePinho at the Dana Farber Cancer Institute, Harvard Medical School. He was an Assistant and then Associate Professor in the Department of Genetics, MD Anderson Cancer Center, before joining the faculty at Yale Medical School as a tenured Associate Professor in 2010. Dr. Chang's research interests focuses on how telomeres, protein/DNA structures at the ends of chromosomes, are properly maintained to protect chromosome ends from engaging a DNA damage response.
Dr. Chang is the recipient of numerous awards, including those from the Howard Hughes Medical Institute, the Ellsion Medical Foundation, the Sidney Kimmel Foundation for Cancer Research, and the Ellis Benson Award from the Academy of Clinical Laboratory Physicians and Scientists. He was elected into the American Society of Clinical Investigation in 2009.
Beginning in 2017, Dr. Chang is also the Associate Dean of Science Education and Quantitative Reasoning and Undergraduate Research at Yale College.
Appointments
Laboratory Medicine
ProfessorPrimaryMolecular Biophysics and Biochemistry
ProfessorSecondaryPathology
ProfessorSecondary
Other Departments & Organizations
- Biochemistry, Quantitative Biology, Biophysics and Structural Biology (BQBS)
- Green College Affiliates
- Laboratory Medicine
- Laboratory Medicine - Education
- Molecular Biophysics and Biochemistry
- Molecular Diagnostics Laboratory
- Molecular Medicine, Pharmacology, and Physiology
- Pathology
- Pathology and Molecular Medicine
- Pathology Research
- Radiobiology and Genome Integrity
- Yale Cancer Center
- Yale Center for Research on Aging (Y-Age)
- Yale Combined Program in the Biological and Biomedical Sciences (BBS)
- Yale Medicine
- Yale Ventures
Education & Training
- Resident
- Brigham & Women's Hospital (2000)
- Resident
- Brigham & Women's Hospital (1998)
- MD
- Cornell University Medical College (1997)
- PhD
- Rockefeller University (1996)
- BS
- Yale University (1988)
Research
Overview
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.
Medical Subject Headings (MeSH)
Research at a Glance
Yale Co-Authors
Publications Timeline
Research Interests
Rekha Rai, PhD
Peili Gu, PhD
Taylor Takasugi
Fengshan Liang, PhD
Lajos Pusztai, MD, DPhil
Telomere-Binding Proteins
DNA Damage
Werner Syndrome
Publications
2024
TRF2–RAP1 represses RAD51-dependent homology-directed telomere repair by promoting BLM-mediated D-loop unwinding and inhibiting BLM–DNA2-dependent 5′-end resection
Liang F, Rai R, Sodeinde T, Chang S. TRF2–RAP1 represses RAD51-dependent homology-directed telomere repair by promoting BLM-mediated D-loop unwinding and inhibiting BLM–DNA2-dependent 5′-end resection. Nucleic Acids Research 2024, gkae642. PMID: 39082275, DOI: 10.1093/nar/gkae642.Peer-Reviewed Original ResearchAltmetricConceptsHomology-directed repairTelomeric D-loopsD-loopChromosome fusionsD-loop formationSingle-stranded telomeric overhangsHomology searchTelomere clusteringTRFH domainPurified proteinBasic domainBlm mutantsProtect telomeresGenomic instabilityTelomeric overhangEnd resectionTRF2Molecular mechanismsTelomereTelomere lossMolecular pathwaysTelomere repairGenomeMutantsRap1
2023
Telomeres cooperate with the nuclear envelope to maintain genome stability
Rai R, Sodeinde T, Boston A, Chang S. Telomeres cooperate with the nuclear envelope to maintain genome stability. BioEssays 2023, 46: e2300184. PMID: 38047499, DOI: 10.1002/bies.202300184.Peer-Reviewed Original ResearchCitationsConceptsNuclear envelopeGenome stabilityNuclear envelope ruptureKu70/Ku80Homology-directed recombinationMammalian telomeresChromosome stabilityNuclear laminsShelterin componentsProtein TRF2Envelope ruptureRepair proteinsTelomeresRap1Recent findingsProteinFunction resultsRecombinationDNA sensingForm structuresLaminsTRF2Ku80DNAHomeostasisPot1b −/− tumors activate G-quadruplex-induced DNA damage to promote telomere hyper-elongation
Takasugi T, Gu P, Liang F, Staco I, Chang S. Pot1b −/− tumors activate G-quadruplex-induced DNA damage to promote telomere hyper-elongation. Nucleic Acids Research 2023, 51: 9227-9247. PMID: 37560909, PMCID: PMC10516629, DOI: 10.1093/nar/gkad648.Peer-Reviewed Original ResearchCitationsAltmetricMeSH Keywords and ConceptsConceptsDNA damage responseDamage responseReplication protein A (RPA) complexDependent DNA damage responseTelomere length homeostasisTelomere maintenance mechanismLength homeostasisTelomerase recruitmentPOT1 proteinsHuman POT1Mouse genomeLength maintenanceFunction disruptsReplicative immortalityTelomeresPOT1 mutationsDNA damageHuman cancersLonger telomeresPOT1bMaintenance mechanismsSerial transplantationA complexesSimilar mechanismMutationsAuthor Correction: Homology directed telomere clustering, ultrabright telomere formation and nuclear envelope rupture in cells lacking TRF2B and RAP1
Rai 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.Peer-Reviewed Original ResearchAltmetricHomology directed telomere clustering, ultrabright telomere formation and nuclear envelope rupture in cells lacking TRF2B and RAP1
Rai 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.Peer-Reviewed Original ResearchCitationsAltmetricMeSH Keywords and ConceptsConceptsDouble-strand breaksNuclear envelopeDistinct DNA repair mechanismsNuclear envelope ruptureKu70/Ku80DNA repair mechanismsDNA-RNA hybridsBRCT domainGenome stabilityPhosphomimetic mutantTelomere formationGenotoxic stressEnvelope ruptureDysfunctional telomeresBasic domainRap1Aberrant laminTelomeresRepair mechanismsLaminsTRF2HomologyProteinShelterinADAR1p110
2021
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.Peer-Reviewed Original ResearchCitationsMeSH Keywords and ConceptsConceptsDNA damage responseTelomerase recruitmentPOT1 proteinsDamage responseATR-dependent DNA damage responseNon-homologous end-joining DNA repair pathwayRecruitment of telomeraseC-strand fillAmino acidsDNA repair pathwaysUnique amino acidsTEN1 (CST) complexTelomere extensionCTC1-STN1Stable heterodimerRepair pathwaysC-terminusDistinct functionsPOT1bPOT1aTelomeresC-strandG-strandTPP1ProteinA Splendid Comet Graces the Northern Sky
Chang S. A Splendid Comet Graces the Northern Sky. Clinical Chemistry 2021, 67: 705-705. DOI: 10.1093/clinchem/hvaa229.Peer-Reviewed Original ResearchAltmetric
2020
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.Peer-Reviewed Original ResearchCitationsAltmetricMeSH KeywordsAminopeptidasesAnimalsBinding SitesCalorimetryCell Cycle ProteinsCytoskeletal ProteinsDipeptidyl-Peptidases and Tripeptidyl-PeptidasesDNA DamageFibroblastsHeLa CellsHistonesHumansMiceMicrocephalyMutationProtein Interaction Domains and MotifsSerine ProteasesShelterin ComplexTelomereTelomere-Binding ProteinsTelomeric Repeat Binding Protein 2Shelterin 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.Peer-Reviewed Original ResearchCitationsMeSH Keywords and Concepts
2019
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.Peer-Reviewed Original ResearchCitationsAltmetricMeSH Keywords and ConceptsMeSH KeywordsAcid Anhydride HydrolasesAdaptor Proteins, Signal TransducingAminopeptidasesAnimalsCell Cycle ProteinsCell Line, TumorCells, CulturedCheckpoint Kinase 1Dipeptidyl-Peptidases and Tripeptidyl-PeptidasesDNA End-Joining RepairDNA Repair EnzymesDNA-Binding ProteinsDNA-Directed DNA PolymeraseExodeoxyribonucleasesHEK293 CellsHumansMiceMRE11 Homologue ProteinMultienzyme ComplexesProliferating Cell Nuclear AntigenSerine ProteasesShelterin ComplexTelomereTelomere-Binding ProteinsTelomeric Repeat Binding Protein 2ConceptsReplication protein AReplisome complexPOT1-TPP1Dysfunctional telomeresDNA damage sensor MRE11-RAD50DNA damage checkpoint responseAlternative non-homologous endNon-homologous endMRN functionChromosome endsMre11-Rad50Checkpoint responseDNA-PKTelomeric overhangMre11 nucleaseTelomere repairEnd resectionRAD-51Repair pathwaysAtaxia telangiectasiaTelomeresC-strandDNA damageReplisomeClaspin
Academic Achievements and Community Involvement
honor Election into the American Society of Clinical Investigation
National AwardAmerican Society of Clinical InvestigationDetails06/11/2009United Stateshonor Ellis Benson Award
National AwardAcademy of Clinical Laboratory Physicians and ScientistsDetails06/20/2007United Stateshonor Sidney Kimmel Foundation for Cancer Research Scholar Award
National AwardSidney Kimmel FoundationDetails06/01/2005United Stateshonor New Scholar in Aging Award
National AwardEllison Medical FoundationDetails02/10/2001United States
Clinical Care
Overview
Clinical Specialties
Fact Sheets
Telomere Research
Learn More on Yale Medicine
Board Certifications
Clinical Pathology
- Certification Organization
- AB of Pathology
- Original Certification Date
- 2003
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News
- April 04, 2018Source: Yale Daily News
Natural killer cell findings could help treat liver cancer
- April 25, 2017
Yale scientist Sandy Chang to oversee undergraduate STEM education
- November 11, 2013
The science of living better, longer
- November 03, 2013
Pressing issues facing the elderly focus of Nov. 7 aging symposium at Yale
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Laboratory Medicine
PO Box 208035
New Haven, CT 06520-8035
United States
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