2020
Oncometabolites suppress DNA repair by disrupting local chromatin signalling
Sulkowski PL, Oeck S, Dow J, Economos NG, Mirfakhraie L, Liu Y, Noronha K, Bao X, Li J, Shuch BM, King MC, Bindra RS, Glazer PM. Oncometabolites suppress DNA repair by disrupting local chromatin signalling. Nature 2020, 582: 586-591. PMID: 32494005, PMCID: PMC7319896, DOI: 10.1038/s41586-020-2363-0.Peer-Reviewed Original ResearchConceptsDNA repairDNA breaksFumarate hydrataseDownstream repair factorsHistone 3 lysine 9Homology-dependent repairPoly (ADP-ribose) polymeraseRecruitment of TIP60Deregulation of metabolismChromatin signalingSuccinate dehydrogenase genesGenome integrityLysine 9Repair factorsDehydrogenase geneEnd resectionIsocitrate dehydrogenase 1Aberrant hypermethylationMechanistic basisSomatic mutationsDehydrogenase 1GenesHuman malignanciesProper executionMutations
2017
SAMHD1 Promotes DNA End Resection to Facilitate DNA Repair by Homologous Recombination
Daddacha W, Koyen AE, Bastien AJ, Head PE, Dhere VR, Nabeta GN, Connolly EC, Werner E, Madden MZ, Daly MB, Minten EV, Whelan DR, Schlafstein AJ, Zhang H, Anand R, Doronio C, Withers AE, Shepard C, Sundaram RK, Deng X, Dynan WS, Wang Y, Bindra RS, Cejka P, Rothenberg E, Doetsch PW, Kim B, Yu DS. SAMHD1 Promotes DNA End Resection to Facilitate DNA Repair by Homologous Recombination. Cell Reports 2017, 20: 1921-1935. PMID: 28834754, PMCID: PMC5576576, DOI: 10.1016/j.celrep.2017.08.008.Peer-Reviewed Original ResearchBi‐allelic alterations in DNA repair genes underpin homologous recombination DNA repair defects in breast cancer
Mutter RW, Riaz N, Ng CK, Delsite R, Piscuoglio S, Edelweiss M, Martelotto LG, Sakr RA, King TA, Giri DD, Drobnjak M, Brogi E, Bindra R, Bernheim G, Lim RS, Blecua P, Desrichard A, Higginson D, Towers R, Jiang R, Lee W, Weigelt B, Reis‐Filho J, Powell SN. Bi‐allelic alterations in DNA repair genes underpin homologous recombination DNA repair defects in breast cancer. The Journal Of Pathology 2017, 242: 165-177. PMID: 28299801, PMCID: PMC5516531, DOI: 10.1002/path.4890.Peer-Reviewed Original ResearchConceptsBreast cancerGermline BRCA1/BRCA2 mutationsBRCA1/BRCA2 mutationsPrecision medicine-based approachPrimary breast cancerTumour-specific DNA repair defectsSporadic breast cancerGermline genetic alterationsBi-allelic lossWhole-exome sequencingSpecific mutational signaturesComprehensive genetic assessmentBRCA2 mutationsLarge-scale state transitionsBi-allelic alterationsCancerGenetic alterationsDNA repair defectsMutational signaturesTherapyAlterationsRepair defectsGene expressionGenetic assessmentHR genes2-Hydroxyglutarate produced by neomorphic IDH mutations suppresses homologous recombination and induces PARP inhibitor sensitivity
Sulkowski PL, Corso CD, Robinson ND, Scanlon SE, Purshouse KR, Bai H, Liu Y, Sundaram RK, Hegan DC, Fons NR, Breuer GA, Song Y, Mishra-Gorur K, De Feyter HM, de Graaf RA, Surovtseva YV, Kachman M, Halene S, Günel M, Glazer PM, Bindra RS. 2-Hydroxyglutarate produced by neomorphic IDH mutations suppresses homologous recombination and induces PARP inhibitor sensitivity. Science Translational Medicine 2017, 9 PMID: 28148839, PMCID: PMC5435119, DOI: 10.1126/scitranslmed.aal2463.Peer-Reviewed Original ResearchConceptsIsocitrate dehydrogenase 1PARP inhibitor sensitivityPossible therapeutic strategiesHomologous recombination defectsTherapeutic strategiesTumor xenograftsInhibitor sensitivityPathologic processesSmall molecule inhibitorsIDH1/2 mutationsTumor progressionIDH2 mutationsMutant IDHPolymerase inhibitorsGlioma cellsTumor cellsHR deficiencyPARP inhibitionIDH mutationsInhibitory effectDehydrogenase 1Neomorphic activityMutant IDH1 enzymeDependent dioxygenasesMutant cells
2016
A single double-strand break system reveals repair dynamics and mechanisms in heterochromatin and euchromatin
Janssen A, Breuer GA, Brinkman EK, van der Meulen AI, Borden SV, van Steensel B, Bindra RS, LaRocque JR, Karpen GH. A single double-strand break system reveals repair dynamics and mechanisms in heterochromatin and euchromatin. Genes & Development 2016, 30: 1645-1657. PMID: 27474442, PMCID: PMC4973294, DOI: 10.1101/gad.283028.116.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCytological TechniquesDNA Breaks, Double-StrandedDNA RepairDrosophila melanogasterEuchromatinHeterochromatinHomologous RecombinationLarvaConceptsDNA double-strand breaksHomologous recombinationGenome stabilityHeterochromatic DSBsEuchromatic DSBsSingle DNA double-strand breakMain DSB repair pathwaysDifferent chromatin domainsLarval imaginal discsDistinct nuclear domainsRepetitive DNA sequencesDSB repair pathwaysDouble-strand breaksChromatin contextChromatin domainsEuchromatic lociPericentromeric heterochromatinChromatin regionsHomologous chromosomesHR templateImaginal discsDSB repairDNA sequencesNuclear domainsRepair pathways
2015
Identification of Novel Radiosensitizers in a High-Throughput, Cell-Based Screen for DSB Repair Inhibitors
Goglia AG, Delsite R, Luz AN, Shahbazian D, Salem AF, Sundaram RK, Chiaravalli J, Hendrikx PJ, Wilshire JA, Jasin M, Kluger HM, Glickman JF, Powell SN, Bindra RS. Identification of Novel Radiosensitizers in a High-Throughput, Cell-Based Screen for DSB Repair Inhibitors. Molecular Cancer Therapeutics 2015, 14: 326-342. PMID: 25512618, PMCID: PMC4326563, DOI: 10.1158/1535-7163.mct-14-0765.Peer-Reviewed Original ResearchConceptsDSB repair inhibitorsDouble-strand breaksDSB repairHomologous recombinationRepair inhibitorsCell-based small molecule screenSuccessful DSB repairDNA-damaging agentsPlate-based formatCell-based screenSmall-molecule screenGenomic integrityTumor cell survivalMammalian cellsHR repairDNA repairMolecule screenReporter systemSecondary assaysCell survivalDNA damageCancer cell linesTumor cellsNovel hitsMost cancer therapies