Joann Sweasy, PhD
Ensign Professor Emeritus of Therapeutic RadiologyCards
Appointments
Contact Info
About
Titles
Ensign Professor Emeritus of Therapeutic Radiology
Biography
I am an expert in the genetics, cell biology, mutagenesis and biochemistry of DNA repair and cancer and have been funded continuously by the NIH since 1994. A major focus of my laboratory is to understand how single nucleotide polymorphisms in DNA repair genes, including genes that function in homology directed repair (HDR), nonhomologous end-joining (NHEJ) and base excision repair (BER) in the germline and somatic tissues impact cancer risk and treatment. We have recently found that RAD51, DNA glycosylase, and POLB germline and somatic tumor variants exhibit functional phenotypes that lead to cellular transformation, genomic instability, and sensitivity or resistance to chemotherapies and ionizing radiation. We have also developed methods to monitor DNA damage in tissue including the presence of single and double strand breaks that lead to PARP activation and trapping. In addition to this, I have focused on determining the roles of DNA repair in a vertebrate organism and have concentrated my studies on mouse models of DNA repair variants. Using these models I have revealed critical roles for DNA repair in preventing the autoimmune disease of lupus. As Associate Director for Basic Research at the Yale Comprehensive Cancer Center, I oversee several pilot and internal grant competitions, am the Principal Investigator of the American Cancer Society Institutional Research Grant, and am currently leading the development of a Translational Research Core which is designed to link patient health records to biospecimens, genomics data, and a living tumor registry.
Appointments
Therapeutic Radiology
EmeritusPrimary
Other Departments & Organizations
- Therapeutic Radiology
- Therapeutic Radiology - Research
- WHRY Pilot Project Program Investigators
- Women's Health Research at Yale
- Yale Ventures
Education & Training
- Postdoctoral Research Fellow
- University of Washington, Seattle, WA (1993)
- PhD
- Rutgers University (1989)
- Senior Staff Microbiologist
- Merck and Company, Rahway, NJ (1989)
- Graduate Research Fellow
- Rutgers University,Piscataway, NJ (1989)
- BA
- Beaver College, Biology and Chemistry (1980)
- Undergraduate Research Assistant,
- Beaver College, Glenside, PA (1980)
- Postdoctoral Fellow
- University of Washington, Seattle, WA
Research
Overview
A major goal of the research conducted in my laboratory is to study the relationship between mutations and cancer. Therefore we concentrate our efforts on studying the mechanism of mutagenesis by a DNA polymerase, polymerase § (Pol §). We employ genetic screens to identify amino acid residues of Pol § that function in promoting the fidelity of DNA synthesis. The Pol § mutant proteins identified in these screens are then analyzed using kinetics to determine the mechanism(s) Pol § employs to synthesize DNA accurately.
We also study the cellular role of Pol § and have shown that Pol § participates in base excision repair and in the process of meiosis. We are pursuing these studies to determine how Pol § makes errors during base excision repair and to identify the role of Pol § in meiosis.Pol § IgG stains discrete foci on mouse chromosome homologs during prophase I of meiosis in mouse spermatocytes. Mouse spermatocytes in early prophase. A, B) Nucleus in late zygonema. Pol §-stained nuclei (red) are on the left; Pol § and Cor I-stained nuclei (white) on the right. C) Nucleus in mid-pachynema. Merged image of Pol § and Cor I-stained nucleus. D) Nucleus in late pachynema and proceeding into diplonema. Merged image of Pol § and Cor I-stained nucleus. Control experiments done in parallel with equivalent chromosomal spreads using preimmune serum or Pol §-depleted IgG fractions yielded no detectable staining (data not shown).
Medical Research Interests
Research at a Glance
Yale Co-Authors
Publications Timeline
Research Interests
Alfred Bothwell, PhD
Caroline Zeiss, DACVP, DACLAM
Ryan B. Jensen, PhD
Timothy Nottoli, PhD
DNA Repair
DNA Replication
Publications
2024
Global screening of base excision repair in nucleosome core particles
Sutton T, Sawyer D, Naila T, Sweasy J, Tomkinson A, Delaney S. Global screening of base excision repair in nucleosome core particles. DNA Repair 2024, 144: 103777. PMID: 39476546, PMCID: PMC11611610, DOI: 10.1016/j.dnarep.2024.103777.Peer-Reviewed Original ResearchCitationsAltmetricConceptsBase excision repairUracil-DNA glycosylaseAP endonuclease 1Nucleosome core particleBase excision repair enzymesAbsence of chromatin remodelingExcision repairDNA polymerase BGenome wide mappingContext of chromatinEukaryotic genomic DNADNA damageCore particlesPolymerase BChromatin remodelingActivities of BER enzymesNick siteGenomic DNAProtein interactionsMutational hotspotsNucleosomal DNADNA glycosylaseGenomic instabilityCellular factorsEntry/exit regionCollapsed State Mediates the Low Fidelity of the DNA Polymerase β I260 Mutant
Fijen C, Chavira C, Alnajjar K, Sawyer D, Sweasy J. Collapsed State Mediates the Low Fidelity of the DNA Polymerase β I260 Mutant. Biochemistry 2024, 63: 2414-2424. PMID: 39299701, PMCID: PMC11448664, DOI: 10.1021/acs.biochem.4c00263.Peer-Reviewed Original ResearchConceptsPol-BI260MForster resonance energy transferNucleotide discriminationConformational changesDNA polymerase BTemperature-sensitive mutationAccurate DNA synthesisReduced fidelityBase excision repairContext-dependent mannerPolymerase BNoncovalent stepPolymerase fidelityBound nucleotideResonance energy transferIncreased mutagenesisGenomic instabilityFinger regionWT proteinExcision repairI260Rate of conformational changeTurnover kineticsMolecular mechanismsModifying the Basicity of the dNTP Leaving Group Modulates Precatalytic Conformational Changes of DNA Polymerase β
Alnajjar K, Wang K, Alvarado-Cruz I, Chavira C, Negahbani A, Nakhjiri M, Minard C, Garcia-Barboza B, Kashemirov B, McKenna C, Goodman M, Sweasy J. Modifying the Basicity of the dNTP Leaving Group Modulates Precatalytic Conformational Changes of DNA Polymerase β. Biochemistry 2024, 63: 1412-1422. PMID: 38780930, PMCID: PMC11155676, DOI: 10.1021/acs.biochem.4c00065.Peer-Reviewed Original ResearchCitationsConceptsDNA polymerase BPolymerase BPol-BBase excision DNA repair pathwayLinear free energy relationshipGapped DNA substratesRemoval of damaged DNA basesFree energy relationshipConformational changesChemical transition stateAccumulation of mutationsDNA repair pathwaysDamaged DNA basesGroup basicityCorrect nucleotideDNA substratesIncoming nucleotideTransition stateEnergy relationshipFingers subdomainRepair pathwaysSubstrate selectivityNucleotideTriphosphate moietyCatalytic functionD239Y germline variant of NTHL1 glycosylase increases susceptibility to colorectal cancer in mice
Masannat T, Ghishan F, Kiela P, Sweasy J. D239Y germline variant of NTHL1 glycosylase increases susceptibility to colorectal cancer in mice. Physiology 2024, 39: 2118. DOI: 10.1152/physiol.2024.39.s1.2118.Peer-Reviewed Original ResearchConceptsInflammation-associated colorectal cancerColorectal cancerDistal colonColon lengthSusceptibility to colorectal cancerC57BL/6 wild-typeMicronucleated normochromatic erythrocytesProximal tumor locationFemale C57BL/6 wild-typeIncreased lifetime riskDextran sulfate sodiumSize of polypsMonitoring body weightKnock-in miceIncreased polyp numberDominant-negative mutationsNormal drinking waterDSS cycleTumor locationWT miceNormochromatic erythrocytesDNA damageWT littermatesColitis scoresRepair mechanismsTemporal coordination of the transcription factor response to H2O2 stress
Jose E, March-Steinman W, Wilson B, Shanks L, Parkinson C, Alvarado-Cruz I, Sweasy J, Paek A. Temporal coordination of the transcription factor response to H2O2 stress. Nature Communications 2024, 15: 3440. PMID: 38653977, PMCID: PMC11039679, DOI: 10.1038/s41467-024-47837-w.Peer-Reviewed Original ResearchCitationsAltmetricMeSH Keywords and ConceptsConceptsGroup of transcription factorsTranscription factorsResponse to H2O2 stressTranscription factor activityCell cycle arrestDose-dependent outcomeRepair oxidative damageOxidative stressDose-dependent activationTime-lapse imagingH2O2 stressCell deathRestoring redox balanceDose-dependentlyTranscriptionRedox balanceGlucose oxidase enzymeNF-kBFactor activity
2020
Role of cysteines in the structure and function of 8-oxoguanine DNA glycosylase
Wang K, Alnajjar K, Maayah M, Sweasy J. Role of cysteines in the structure and function of 8-oxoguanine DNA glycosylase. 2020 DOI: 10.1021/scimeetings.0c07078.Peer-Reviewed Original Research
2017
Defective Nucleotide Release by DNA Polymerase β Mutator Variant E288K Is the Basis of Its Low Fidelity
Mahmoud MM, Schechter A, Alnajjar KS, Huang J, Towle-Weicksel J, Eckenroth BE, Doublié S, Sweasy JB. Defective Nucleotide Release by DNA Polymerase β Mutator Variant E288K Is the Basis of Its Low Fidelity. Biochemistry 2017, 56: 5550-5559. PMID: 28945359, PMCID: PMC5654646, DOI: 10.1021/acs.biochem.7b00869.Peer-Reviewed Original ResearchCitationsAltmetricMeSH Keywords and ConceptsMeSH KeywordsAmino Acid SubstitutionBiocatalysisColonic NeoplasmsDNADNA Polymerase betaDNA RepairDNA ReplicationEnzyme StabilityFluorescent DyesHumansKineticsModels, MolecularMutagenesis, Site-DirectedMutationNaphthalenesulfonatesNeoplasm ProteinsP-DimethylaminoazobenzeneProtein ConformationProtein Interaction Domains and MotifsProtein RefoldingRecombinant ProteinsSubstrate SpecificityDNA Polymerase β Cancer-Associated Variant I260M Exhibits Nonspecific Selectivity toward the β–γ Bridging Group of the Incoming dNTP
Alnajjar KS, Negahbani A, Nakhjiri M, Krylov IS, Kashemirov BA, McKenna CE, Goodman MF, Sweasy JB. DNA Polymerase β Cancer-Associated Variant I260M Exhibits Nonspecific Selectivity toward the β–γ Bridging Group of the Incoming dNTP. Biochemistry 2017, 56: 5449-5456. PMID: 28862868, PMCID: PMC5634933, DOI: 10.1021/acs.biochem.7b00713.Peer-Reviewed Original ResearchCitationsDNA repair and systemic lupus erythematosus
Meas R, Burak MJ, Sweasy JB. DNA repair and systemic lupus erythematosus. DNA Repair 2017, 56: 174-182. PMID: 28623091, PMCID: PMC5543809, DOI: 10.1016/j.dnarep.2017.06.020.Peer-Reviewed Original ResearchCitationsAltmetricMeSH Keywords and ConceptsConceptsSystemic lupus erythematosusDevelopment of lupusLupus erythematosusGenetic predispositionChronic autoimmune diseaseAutoimmune diseasesMonozygotic twin concordanceFamilial aggregation studiesImmune systemLupusPotential associationCommon risk allelesRisk allelesDNA repair genesEnvironmental exposuresAberrant DNA repairErythematosusDNA repairTwin concordanceRepair genesCurrent knowledgeRepairAggregation studiesPredispositionDiseaseA Change in the Rate-Determining Step of Polymerization by the K289M DNA Polymerase β Cancer-Associated Variant
Alnajjar KS, Garcia-Barboza B, Negahbani A, Nakhjiri M, Kashemirov B, McKenna C, Goodman MF, Sweasy JB. A Change in the Rate-Determining Step of Polymerization by the K289M DNA Polymerase β Cancer-Associated Variant. Biochemistry 2017, 56: 2096-2105. PMID: 28326765, PMCID: PMC5522186, DOI: 10.1021/acs.biochem.6b01230.Peer-Reviewed Original ResearchCitations
Academic Achievements & Community Involvement
honor Argall and Anna Hull Award
UnknownDetailsUnited Stateshonor American Cancer Society Junior Faculty Research Award
UnknownDetailsUnited Stateshonor Donaghue Investigator Award
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News
News
- May 23, 2024
Yale Cancer Center Joins Hill Day to Advocate for Investment in Cancer Research
- September 19, 2017
Scientist Joann Sweasy awarded Postdoctoral Mentoring Prize
- January 31, 2017
Appointments to ongoing endowed professorships
- January 01, 2017
Boosting Mutations to Kill Cancer