Joann Sweasy, PhD
Ensign Professor Emeritus of Therapeutic RadiologyCards
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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)
- Graduate Research Fellow
- Rutgers University,Piscataway, NJ (1989)
- BA
- Beaver College, Biology and Chemistry (1980)
- Undergraduate Research Assistant,
- Beaver College, Glenside, PA (1980)
Research
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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
ORCID
0000-0002-4503-0284
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
Publications
2026
The S180R Human Germline Variant of DNA Polymerase β Is a Low Fidelity Enzyme with Reduced Flexibility of the Fingers Domain
Sawyer D, Eckenroth B, Chavira C, Alnajjar K, Hanley J, Dragon J, Doublié S, Sweasy J. The S180R Human Germline Variant of DNA Polymerase β Is a Low Fidelity Enzyme with Reduced Flexibility of the Fingers Domain. Biochemistry 2026, 65: 270-283. PMID: 41524291, PMCID: PMC13105415, DOI: 10.1021/acs.biochem.5c00628.Peer-Reviewed Original ResearchAltmetricMeSH Keywords and ConceptsConceptsLow-fidelity variantsBase excision repair pathwayPol-BFinger domainGenetic variantsLow-fidelity enzymesDNA polymerase BNon-homologous end-joining pathwayAmino acid alterationsRate of nucleotide incorporationEnd-joining pathwayExcision repair pathwayBase excision repairDNTP-binding pocketPolymerase BIncorrect nucleotidesFidelity enzymesMutation accumulationNucleotide selectivityPolymerase functionNucleotide incorporationDNA repairDNTP bindingAcid alterationsRepair DNA
2025
Protein–Protein Interactions in Base Excision Repair
Rathnaiah G, Sweasy J. Protein–Protein Interactions in Base Excision Repair. Biomolecules 2025, 15: 890. PMID: 40563529, PMCID: PMC12190888, DOI: 10.3390/biom15060890.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsCitationsMeSH Keywords and ConceptsConceptsProtein-protein interactionsBase excision repairPolynucleotide kinase-phosphataseApurinic/apyrimidinic endonuclease 1X-ray repair cross-complementing protein 1Single-nucleotide base excision repairBase excision repair componentsExcision repairDNA polymerase BBase excision repair pathwayRepair of damaged basesDNA repair processesCore enzymePolymerase BDNA intermediatesProtein-proteinDamaged basesSingle-nucleotideDNA glycosylaseMolecular networksMolecular underpinningsDNAFunctional evidenceProtein 1Enzyme
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 ResearchCitationsConceptsPol-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 ResearchCitationsAltmetricConceptsDNA 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 functionTemporal 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
2017
DNA Polymerase Beta Germline Variant Confers Cellular Response to Cisplatin Therapy
Nemec AA, Abriola L, Merkel JS, de Stanchina E, DeVeaux M, Zelterman D, Glazer PM, Sweasy JB. DNA Polymerase Beta Germline Variant Confers Cellular Response to Cisplatin Therapy. Molecular Cancer Research 2017, 15: 269-280. PMID: 28074003, PMCID: PMC5334281, DOI: 10.1158/1541-7786.mcr-16-0227-t.Peer-Reviewed Original ResearchCitationsMeSH Keywords and ConceptsConceptsPrognostic biomarker potentialMouse xenograft modelLung cancer cellsPoor prognosisTreatment of cancerLung cancerSpecific chemotherapyXenograft modelPromising biomarkerMouse xenograftsMutational statusCancer ResChemotherapyGermline mutationsNucleotide excision repair pathwayBiomarker potentialCancer chemotherapyCancer treatmentCarrier statusCisplatinCancer cellsTumorsCancerTreatmentCell death
2016
The Tumor-Associated Variant RAD51 G151D Induces a Hyper-Recombination Phenotype
Marsden CG, Jensen RB, Zagelbaum J, Rothenberg E, Morrical SW, Wallace SS, Sweasy JB. The Tumor-Associated Variant RAD51 G151D Induces a Hyper-Recombination Phenotype. PLOS Genetics 2016, 12: e1006208. PMID: 27513445, PMCID: PMC4981402, DOI: 10.1371/journal.pgen.1006208.Peer-Reviewed Original ResearchCitationsAltmetricMeSH Keywords and ConceptsMeSH KeywordsBRCA2 ProteinBreast NeoplasmsChromosome AberrationsDNA Breaks, Double-StrandedDNA DamageDNA RepairDoxorubicinFemaleGene Expression Regulation, NeoplasticGenomic InstabilityHumansMCF-7 CellsMitomycinMutationRad51 RecombinaseRadiation, IonizingRecombinational DNA RepairSister Chromatid ExchangeConceptsHuman breast epithelial cellsBreast epithelial cellsSister chromatid exchangesBreast carcinomaDrug resistanceMitomycin CEpithelial cellsChromosomal aberrationsHigh levelsChromatid exchangesRepairSomatic variantsRAD51 variantsDNA damageMultiple DNA damaging agentsDNA damaging agentsPresence of RPAPhenotypeCellsCarcinomaExpressionDNA double-strand breaksDamaging agentsLevelsVariants
2014
Mutation of POLB Causes Lupus in Mice
Senejani AG, Liu Y, Kidane D, Maher SE, Zeiss CJ, Park HJ, Kashgarian M, McNiff JM, Zelterman D, Bothwell AL, Sweasy JB. Mutation of POLB Causes Lupus in Mice. Cell Reports 2014, 6: 1-8. PMID: 24388753, PMCID: PMC3916967, DOI: 10.1016/j.celrep.2013.12.017.Peer-Reviewed Original ResearchCitationsAltmetricMeSH Keywords and ConceptsConceptsSystemic lupus erythematosusLupus-like diseaseLupus erythematosusAutoimmune pathologyMouse modelGenome-wide association studiesPol β activityDecreased expressionMutant miceUnderlying causeMicePrevious genome-wide association studyΒ activityDNA polymerase activityReplication studyExcision repair pathwayImmune diversitySomatic hypermutationBase excision repair pathwayAssociation studiesErythematosusLupusPolymerase activityExpressionKey enzyme
2012
Y265C DNA polymerase beta knockin mice survive past birth and accumulate base excision repair intermediate substrates
Senejani AG, Dalal S, Liu Y, Nottoli TP, McGrath JM, Clairmont CS, Sweasy JB. Y265C DNA polymerase beta knockin mice survive past birth and accumulate base excision repair intermediate substrates. Proceedings Of The National Academy Of Sciences Of The United States Of America 2012, 109: 6632-6637. PMID: 22493258, PMCID: PMC3340078, DOI: 10.1073/pnas.1200800109.Peer-Reviewed Original ResearchCitationsMeSH Keywords and ConceptsConceptsDNA polymerase activityWT littermatesKnockin miceMiceMouse embryo fibroblastsChromosomal aberrationsWT mouse embryo fibroblastsNormal Mendelian ratioSlow proliferationPolymerase activityBirthΒ variantCell deathEmbryo fibroblastsWT cellsExcision repair pathwayDNA repair systemsCellular metabolismBase excision repair pathwayFibroblastsHoursHigh levelsHomozygous mutantsKey players
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