DNA Repair; Genetics; Radiation; Mutagenesis; Gene Targeting; Radiation Oncology; Recombinational DNA Repair
Therapeutic Radiology: Glazer Lab | Radiobiology | Therapeutic Radiology - Research
Skin Diseases Research Center, Yale
WHRY Pilot Project Program Investigators
Gene targeting via triple helix formation: From an interest in studying cellular DNA repair and recombination pathways, we recognized the utility of DNA triple helix formation as a mechanism for the site-specific induction of recombination in human cells. We have recently demonstrated that triplex forming oligonucleotides can be used to mediate targeted modification of human disease-related genes. We are currently optimizing this approach for application in human hematopoietic stem cells and in mouse models of human genetic diseases.
Tumor hypoxia, genetic instability, and cancer therapy: We discovered that tumor hypoxia is a key driver of genetic instability in human cancer cells. Mechanistically, we determined that this instability arises because of suppression of the DNA mismatch repair and homology dependent repair pathways, due to specific repression of the MLH1 and BRCA1, genes, respectively. This down-regulation of DNA repair in hypoxic cancer cells renders them vulnerable to therapeutic strategies that exploit the specific repair deficiencies, providing the basis for novel, rationally designed cancer therapies.
Specialized Terms: Gene targeting and gene therapy; Genetic instability in cancer; Mutagenesis; DNA repair; Radiation resistance; Cellular responses to radiation
Extensive Research DescriptionGene targeting via triple helix formation
From an interest in studying cellular DNA repair and recombination pathways, we recognized the utility of DNA triple helix formation as a mechanism for the site-specific introduction of DNA damage in mammalian cells. Using psoralen-conjugated triplex-forming oligonucleotides, we initially demonstrated the feasibility of triplex-targeted mutagenesis in several model systems. We were able to determine conditions under which triplex oligonucleotides can enter cells and efficiently bind to and modify a target site within cells, leading to base pair specific mutations. Experiments with oligonucleotides not tethered to a reactive agent but capable of high affinity third strand binding revealed that triple helix formation can induce DNA repair and recombination in mammalian cells. This work has raised the possibility of using triplex formation as both a gene knock out and a gene correction modality. It has also suggested that unusual DNA structures may provoke repair activity and may contribute to genomic instability. We are currently studying the feasibility of targeting chromosomal genes using this approach, either by directly inducing mutations in the target gene or by stimulating recombination in a site-directed manner.
Tumor hypoxia, genetic instability, and tumor progression
We hypothesized that that acquired genetic instability in cancer cells may arise from the dysregulation of critical DNA repair pathways due to cell stresses within the tumor microenvironment such as hypoxia. We initially confirmed this hypothesis by measuring mutation frequencies in experimental tumors using a lambda-based chromosomal shuttle vector reporter system. To elucidate the mechanism underlying this phenomenon we used a microarray-based approach to screen for hypoxia-regulated DNA repair pathways. We found that hypoxia specifically down-regulates the expression of Mlh1 and Rad51, key mediators of DNA mismatch repair and of homologous recombination in mammalian cells, respectively. Down-regulation of Mlh1 and Rad51 expression by hypoxia was observed in numerous cell lines from a wide range of tissues, and was not correlated with cell cycle profile or hypoxia-inducible factor expression. Rad51 down-regulation was also detected in vivo in the tumor microenvironment, as we observed consistent inverse correlations between hypoxia-marker staining and Rad51 expression by immunofluorescence in cervical and prostate cancer xenograft models. We propose the existence of a hypoxic phenotype in solid tumors, characterized by decreased expression of the critical DNA repair genes, Mlh1 and Rad51, representing a novel mechanism of acquired genetic instability in the tumor microenvironment and dysregulated DNA damage response in cancer cells.
Mechanism of cancer cell killing by cisplatin
Cisplatin is one of the most widely used cancer chemotherapy agents, but its mechanism of action is not fully understood. Current models suggest that cell killing by cisplatin occurs in a cell-autonomous manner via formation of platinum-DNA adducts that, if not removed by DNA repair, block transcription and replication. We have found that there is a separate cell-interdependent pathway of cisplatin killing in which damaged cells can transmit a death signal to neighboring cells. This signal is produced within the damaged cell by the kinase function of the Ku70, Ku80, and DNA-PK complex and is conveyed to the recipient cell by direct cell-to-cell communication through gap junctions. Our findings suggest that DNA-PK activity and gap junction expression in human cancers may influence the clinical response to cisplatin. In addition, strategies to manipulate these cellular components in conjunction with cisplatin treatment may provide new approaches to cancer therapy.
DNA repair and mutagenesis in transgenic mice
We are carrying out mutagenesis studies using a lambda phage vector construct as a chromosomal shuttle vector in transgenic mice and mouse cells. We have determined that p53 overexpression can lessen mutagenesis by UV light, and we have examined the spectrum of x-ray-induced point mutations in mouse cells. In transgenic mice, we have found that locus specific effects can profoundly influence the mutation frequency in a reporter gene, and we have begun to study tissue-dependent variations in the pattern of spontaneous mutagenesis. Recently, we have created doubly transgenic mice carrying not only the lambda shuttle vector for reporting mutations but also a targeted disruption of the mouse PMS2 gene, a homolog of the E. coli mutL gene involved in mismatch repair. The human homolog of this gene has been associated with hereditary colon cancer. We are examining genetic instability in these mice using the lambda vector system. Preliminary work has shown elevated levels of mutation in all tissues tested, in contrast to the limited tissue distribution of cancer in the animals, a difference which highlights the complexity of cancer etiology.
- Gene targeting and gene therapy for human genetic diseases via triple helix formation.
- Tumor hypoxia, genetic instability, and cancer therapy.
- DNA repair and mutagenesis in transgenic mice.
2-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. 2017
In vivo correction of anemia in β-thalassemic mice by PNA-mediated gene editing with nanoparticle delivery.
Bahal, R., McNeer, N.A., Quijano, E., Liu, Y., Sulkowski, P., Turchick, A., Lu, Y-C., Bhunia, D.C., Manna, A., Greiner, D.L., Brehm, M.A., Cheng, C.J., López-Giráldez, F., Ricciardi, A., Beloor, J., Krause, D.S., Kumar, P., Gallagher, P.G., Braddock, D.T., Saltzman, W.M., Ly, D.H., and Glazer, P.M. 2016
Nanoparticles that deliver triplex-forming peptide nucleic acid molecules correct F508del CFTR in airway epithelium.
McNeer, N.A., Anandalingam, K., Fields, R.J., Caputo, C., Kopic, S., Gupta, A., Quijano, E., Polikoff, L., Kong, Y., Bahal, R., Geibel, J.P., Glazer, P.M., Saltzman, W.M. & Egan, M.E. 2015
MicroRNA silencing for cancer therapy targeted to the tumor microenvironment.
Cheng CJ, Bahal R, Babar IA, Pincus Z, Barrera F, Liu C, Svoronos A, Braddock D, Glazer PM, Engelman DM, Saltzman WM, Slack FJ. 2015
Silencing of the DNA mismatch repair gene, MLH1 induced by hypoxic stress in a pathway dependent on the histone demethylase, LSD1.
Lu Y, Wajapeyee N, Turker MS and Glazer, P.M. 2014
The cytotoxicity of (-)-lomaiviticin A arises from induction of double-strand breaks in DNA.
Colis L, Woo C, Hegan D, Li Z, Glazer PM, Herzon S. 2014
Hypoxic stress facilitates acute activation and chronic down-regulation of Fanconi anemia proteins.
Scanlon SE, Glazer PM 2014
Radiation sensitivity and sensitization in melanoma.
Shahbazian D, Bindra RS, Kluger HM, Glazer PM. (2013) Radiation sensitivity and sensitization in melanoma.Pigment Cell Melanoma Res. 2013 Jul 22.
Targeting cancer with a lupus autoantibody.
Hansen JE, Chan G, Liu Y, Hegan DC, Dalal S, Dray E, Kwon Y, Xu Y, Xu X, Peterson-Roth E, Geiger E, Liu Y, Gera J, Sweasy JB, Sung P, Rockwell S, Nishimura RN, Weisbart RH and Glazer PM: Targeting cancer with a lupus autoantibody. Sci Transl Med. 2012 Oct 24;4 (157) :157ra142. PMID: 23100628
Systemic delivery of triplex-forming PNA and donor DNA by nanoparticles mediates site-specific genome editing of human hematopoietic cells in vivo.
McNeer NA, Schleifman EB, Cuthbert A, Brehm M, Jackson A, Cheng C, Anandalingam K, Kumar P, Shultz LD, Greiner DL, Mark Saltzman W and Glazer PM: Systemic delivery of triplex-forming PNA and donor DNA by nanoparticles mediates site-specific genome editing of human hematopoietic cells in vivo. Gene Ther. 2012 Oct 18; Epub 2012 Oct 18. PMID: 23076379
Hypoxia-induced epigenetic regulation and silencing of the BRCA1 promoter.
Lu Y, Chu A, Turker MS and Glazer PM: Hypoxia-induced epigenetic regulation and silencing of the BRCA1 promoter. Mol Cell Biol. 2011 Aug;31 (16) :3339-50. Epub 2011 Jun 13. PMID: 21670155
Inhibition of poly(ADP-ribose) polymerase down-regulates BRCA1 and RAD51 in a pathway mediated by E2F4 and p130.
Hegan, D.C., Lu, Y., Stachelek, G.C., Crosby, M.E., Bindra, R.S. & Glazer, P.M. 2010
MicroRNA regulation of DNA repair gene expression in hypoxic stress.
Crosby ME, Kulshreshtha R, Ivan M, Glazer PM. MicroRNA regulation of DNA repair gene expression in hypoxic stress. Cancer Res. 2009 Feb 169(3):1221-9. Epub 2009 Jan 13. Erratum in: Cancer Res. 2009 Apr 169(7):3240.
Repair of DNA lesions associated with triplex-forming oligonucleotides.
Chin JY, Glazer PM. Repair of DNA lesions associated with triplex-forming oligonucleotides. Mol Carcinog. 2009 Apr48(4):389-99. Review.
Correction of a splice-site mutation in the beta-globin gene stimulated by triplex-forming peptide nucleic acids.
Chin, J.Y., Kuan, J.Y., Lonkar, P.S., Krause, D.S., Seidman, M.M., Peterson, K.R., Nielsen, P.E., Kole, R. and Glazer, P.M. 2008
Repression of RAD51 gene expression by E2F4/p130 in hypoxia.
Bindra, R.S. and Glazer, P.M. (2007). Repression of RAD51 gene expression by E2F4/p130 in hypoxia. Oncogene 26:2048-57.
Down-regulation of Rad51 and decreased homologous recombination in hypoxic cancer cells.
Bindra, R.S., Schaffer, P.J., Meng, A., Woo, J., Maseide, K., Roth, M.E., Lizardi, P, Hedley, D.W., Bristow, R.G., and Glazer, P.M. 2004
Cell-interdependent cisplatin killing by Ku/DNA-PK signaling transduced through gap junctions.
Jensen, R. and Glazer, P.M. 2004
Site-directed recombination via bifunctional PNA-DNA conjugates.
Rogers, F.A., Vasquez, K.M., Egholm, M., and Glazer, P.M. 2002
Human XPA and RPA DNA repair proteins participate in specific recognition of triplex-induced helical distortions.
Vasquez, K.M., Christensen, J., Li, L., Finch, R.A. and Glazer, P.M. 2002
ATM-dependent expression of the IGF-I receptor in a pathway regulating radiation response.
Peretz S., Jensen R., Baserga R. and Glazer P.M. 2001
Specific mutations induced by triplex-forming oligonucleotides in mice.
Vasquez, K.M., Narayanan, L., and Glazer, P.M. (2000). Specific mutations induced by triplex-forming oligonucleotides in mice. Science 290:530-3.
Diminished DNA repair and elevated mutagenesis in mammalian cells exposed to hypoxia and low pH.
Yuan, J., Narayanan, L., Rockwell, S., and Glazer, P.M. 2000
Targeted correction of an episomal gene in mammalian cells by a short DNA fragment tethered to a triplex-forming oligonucleotide.
Chan, P.P., Lin, M., Faruqi, A.F., Powell, J., Seidman, M.M., and Glazer, P.M. 1999
Targeted gene knockout mediated by triple helix forming oligonucleotides.
Majumdar, A., Khorlin, A., Dyatkina, N., Lin, F.-L. M., Powell, J., Liu, J., Fei, Z., Khripine, Y., Watanabe, K.A., George, J., Glazer, P.M., and Seidman, M.M. 1998
Peptide nucleic acid-targeted mutagenesis of a chromosomal gene in mouse cells.
Faruqi, A.F., Egholm, M., and Glazer, P.M. 1998
Insulin-like growth factor-I receptor overexpression mediates cellular radioresistance and local breast cancer recurrence after lumpectomy and radiation.
Turner, B.C., Haffty, B.G., Narayanan, L., Yuan, J., Havre, P.A., Gumbs, A.A., Kaplan, L., Burgaud, J.-L., Carter, D., Baserga, R., and Glazer, P.M. 1997
Elevated levels of mutation in multiple tissues of mice deficient in the DNA mismatch repair gene, PMS2.
Narayanan, L., Fritzell, J.A., Baker, S.M., Liskay, R.M. and Glazer, P.M. 1997
Genetic instability induced by the tumor microenvironment.
Reynolds, T.Y., Rockwell, S., and Glazer, P.M. 1996
Recombination induced by triple helix-targeted DNA damage in mammalian cells.
Faruqi, A.F., Seidman, M.M., Segal, D.J., Carroll, D., and Glazer, P.M. 1996
Mutagenesis in mammalian cells induced by triple helix formation and transcription-coupled repair.
Wang, G., Seidman, M.M., and Glazer, P.M. 1996
Targeted mutagenesis in mammalian cells mediated by intracellular triple helix formation.
Wang, G., Levy, D.D., Seidman, M.M. and Glazer, P.M. 1995
High efficiency, restriction-deficient in vitro packaging extracts for bacteriophage lambda DNA using a new E. coli lysogen.
Gunther, E.J., Murray, N.E. and Glazer, P.M. 1993
Targeted mutagenesis of DNA using triple helix-forming oligonucleotides linked to psoralen.
Havre, P.A., Gunther, E.J., Gasparro, F.P. and Glazer, P.M. 1993
Full List of PubMed Publications
- Ricciardi AS, Quijano E, Putman R, Saltzman WM, Glazer PM: Peptide Nucleic Acids as a Tool for Site-Specific Gene Editing. Molecules. 2018 Mar 11; 2018 Mar 11. PMID: 29534473
- Kim H, Lin Q, Glazer PM, Yun Z: The hypoxic tumor microenvironment in vivo selects the cancer stem cell fate of breast cancer cells. Breast Cancer Res. 2018 Mar 6; 2018 Mar 6. PMID: 29510720
- Scanlon SE, Hegan DC, Sulkowski PL, Glazer PM: Suppression of homology-dependent DNA double-strand break repair induces PARP inhibitor sensitivity in VHL-deficient human renal cell carcinoma. Oncotarget. 2018 Jan 12; 2017 Dec 19. PMID: 29435132
- Quijano E, Bahal R, Ricciardi A, Saltzman WM, Glazer PM: Therapeutic Peptide Nucleic Acids: Principles, Limitations, and Opportunities . Yale J Biol Med. 2017 Dec; 2017 Dec 19. PMID: 29259523
- Gupta A, Quijano E, Liu Y, Bahal R, Scanlon SE, Song E, Hsieh WC, Braddock DE, Ly DH, Saltzman WM, Glazer PM: Anti-tumor Activity of miniPEG-γ-Modified PNAs to Inhibit MicroRNA-210 for Cancer Therapy. Mol Ther Nucleic Acids. 2017 Dec 15; 2017 Sep 12. PMID: 29246289
- Turchick A, Hegan DC, Jensen RB, Glazer PM: A cell-penetrating antibody inhibits human RAD51 via direct binding. Nucleic Acids Res. 2017 Nov 16. PMID: 29036688
- Scanlon SE, Scanlon CD, Hegan DC, Sulkowski PL, Glazer PM: Nickel induces transcriptional down-regulation of DNA repair pathways in tumorigenic and non-tumorigenic lung cells. Carcinogenesis. 2017 Jun 1. PMID: 28472268
- 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. Mol Cancer Res. 2017 Mar; 2017 Jan 10. PMID: 28074003
- 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. Sci Transl Med. 2017 Feb 1. PMID: 28148839
- Gupta A, Bahal R, Gupta M, Glazer PM, Saltzman WM: Nanotechnology for delivery of peptide nucleic acids (PNAs). J Control Release. 2016 Oct 28; 2016 Jan 8. PMID: 26776051
- Bahal R, Ali McNeer N, Quijano E, Liu Y, Sulkowski P, Turchick A, Lu YC, Bhunia DC, Manna A, Greiner DL, Brehm MA, Cheng CJ, López-Giráldez F, Ricciardi A, Beloor J, Krause DS, Kumar P, Gallagher PG, Braddock DT, Mark Saltzman W, Ly DH, Glazer PM: In vivo correction of anaemia in β-thalassemic mice by γPNA-mediated gene editing with nanoparticle delivery. Nat Commun. 2016 Oct 26; 2016 Oct 26. PMID: 27782131
- Czochor JR, Sulkowski P, Glazer PM: miR-155 Overexpression Promotes Genomic Instability by Reducing High-fidelity Polymerase Delta Expression and Activating Error-Prone DSB Repair. Mol Cancer Res. 2016 Apr; 2016 Feb 5. PMID: 26850462
- Stachelek GC, Peterson-Roth E, Liu Y, Fernandez RJ 3rd, Pike LR, Qian JM, Abriola L, Hoyer D, Hungerford W, Merkel J, Glazer PM: YU238259 Is a Novel Inhibitor of Homology-Dependent DNA Repair That Exhibits Synthetic Lethality and Radiosensitization in Repair-Deficient Tumors. Mol Cancer Res. 2015 Oct; 2015 Jun 26. PMID: 26116172
- Scanlon SE, Glazer PM: Multifaceted control of DNA repair pathways by the hypoxic tumor microenvironment. DNA Repair (Amst). 2015 Aug; 2015 May 1. PMID: 25956861
- Weisbart RH, Chan G, Jordaan G, Noble PW, Liu Y, Glazer PM, Nishimura RN, Hansen JE: DNA-dependent targeting of cell nuclei by a lupus autoantibody. Sci Rep. 2015 Jul 9; 2015 Jul 9. PMID: 26156563
- Colis LC, Hegan DC, Kaneko M, Glazer PM, Herzon SB: Mechanism of action studies of lomaiviticin A and the monomeric lomaiviticin aglycon. Selective and potent activity toward DNA double-strand break repair-deficient cell lines. J Am Chem Soc. 2015 May 6; 2015 Apr 22. PMID: 25849366
- McNeer NA, Anandalingam K, Fields RJ, Caputo C, Kopic S, Gupta A, Quijano E, Polikoff L, Kong Y, Bahal R, Geibel JP, Glazer PM, Saltzman WM, Egan ME: Nanoparticles that deliver triplex-forming peptide nucleic acid molecules correct F508del CFTR in airway epithelium. Nat Commun. 2015 Apr 27; 2015 Apr 27. PMID: 25914116
- Fields RJ, Quijano E, McNeer NA, Caputo C, Bahal R, Anandalingam K, Egan ME, Glazer PM, Saltzman WM: Modified poly(lactic-co-glycolic acid) nanoparticles for enhanced cellular uptake and gene editing in the lung. Adv Healthc Mater. 2015 Feb 18; 2014 Aug 25. PMID: 25156908
- Cheng CJ, Bahal R, Babar IA, Pincus Z, Barrera F, Liu C, Svoronos A, Braddock DT, Glazer PM, Engelman DM, Saltzman WM, Slack FJ: MicroRNA silencing for cancer therapy targeted to the tumour microenvironment. Nature. 2015 Feb 5; 2014 Nov 17. PMID: 25409146
- Reza F, Glazer PM: Therapeutic genome mutagenesis using synthetic donor DNA and triplex-forming molecules. Methods Mol Biol. 2015. PMID: 25408401
- Gupta R, Liu AY, Glazer PM, Wajapeyee N: LKB1 preserves genome integrity by stimulating BRCA1 expression. Nucleic Acids Res. 2015 Jan; 2014 Dec 8. PMID: 25488815
- Lu Y, Wajapeyee N, Turker MS, Glazer PM: Silencing of the DNA mismatch repair gene MLH1 induced by hypoxic stress in a pathway dependent on the histone demethylase LSD1. Cell Rep. 2014 Jul 24; 2014 Jul 17. PMID: 25043185
- Czochor JR, Glazer PM: microRNAs in cancer cell response to ionizing radiation. Antioxid Redox Signal. 2014 Jul 10; 2014 Feb 4. PMID: 24206455
- Zhang M, Xiang S, Joo HY, Wang L, Williams KA, Liu W, Hu C, Tong D, Haakenson J, Wang C, Zhang S, Pavlovicz RE, Jones A, Schmidt KH, Tang J, Dong H, Shan B, Fang B, Radhakrishnan R, Glazer PM, Matthias P, Koomen J, Seto E, Bepler G, Nicosia SV, Chen J, Li C, Gu L, Li GM, Bai W, Wang H, Zhang X: HDAC6 deacetylates and ubiquitinates MSH2 to maintain proper levels of MutSα. Mol Cell. 2014 Jul 3; 2014 May 29. PMID: 24882211
- Scanlon SE, Glazer PM: Hypoxic stress facilitates acute activation and chronic downregulation of fanconi anemia proteins. Mol Cancer Res. 2014 Jul; 2014 Mar 31. PMID: 24688021
- Colis LC, Woo CM, Hegan DC, Li Z, Glazer PM, Herzon SB: The cytotoxicity of (-)-lomaiviticin A arises from induction of double-strand breaks in DNA. Nat Chem. 2014 Jun; 2014 May 11. PMID: 24848236
- Bahal R, Quijano E, McNeer NA, Liu Y, Bhunia DC, Lopez-Giraldez F, Fields RJ, Saltzman WM, Ly DH, Glazer PM: Single-stranded γPNAs for in vivo site-specific genome editing via Watson-Crick recognition. Curr Gene Ther. 2014. PMID: 25174576
- Ricciardi AS, McNeer NA, Anandalingam KK, Saltzman WM, Glazer PM: Targeted genome modification via triple helix formation. Methods Mol Biol. 2014. PMID: 25030921
- Reza F, Glazer PM: Triplex-mediated genome targeting and editing. Methods Mol Biol. 2014. PMID: 24557900
- Schleifman EB, Glazer PM: Peptide nucleic acid-mediated recombination for targeted genomic repair and modification. Methods Mol Biol. 2014. PMID: 24297362
- Glazer PM, Hegan DC, Lu Y, Czochor J, Scanlon SE: Hypoxia and DNA repair. Yale J Biol Med. 2013 Dec 13; 2013 Dec 13. PMID: 24348208
- Schleifman EB, McNeer NA, Jackson A, Yamtich J, Brehm MA, Shultz LD, Greiner DL, Kumar P, Saltzman WM, Glazer PM: Site-specific Genome Editing in PBMCs With PLGA Nanoparticle-delivered PNAs Confers HIV-1 Resistance in Humanized Mice. Mol Ther Nucleic Acids. 2013 Nov 19; 2013 Nov 19. PMID: 24253260
- Shahbazian D, Bindra RS, Kluger HM, Glazer PM: Radiation sensitivity and sensitization in melanoma. Pigment Cell Melanoma Res. 2013 Nov; 2013 Aug 12. PMID: 23870422
- Chin JY, Reza F, Glazer PM: Triplex-forming peptide nucleic acids induce heritable elevations in gamma-globin expression in hematopoietic progenitor cells. Mol Ther. 2013 Mar; 2013 Jan 22. PMID: 23337982
- Neumeister VM, Sullivan CA, Lindner R, Lezon-Geyda K, Li J, Zavada J, Martel M, Glazer PM, Tuck DP, Rimm DL, Harris L: Hypoxia-induced protein CAIX is associated with somatic loss of BRCA1 protein and pathway activity in triple negative breast cancer. Breast Cancer Res Treat. 2012 Nov; 2012 Sep 14. PMID: 22976806
- Hansen JE, Chan G, Liu Y, Hegan DC, Dalal S, Dray E, Kwon Y, Xu Y, Xu X, Peterson-Roth E, Geiger E, Liu Y, Gera J, Sweasy JB, Sung P, Rockwell S, Nishimura RN, Weisbart RH, Glazer PM: Targeting cancer with a lupus autoantibody. Sci Transl Med. 2012 Oct 24. PMID: 23100628
- Rockwell S, Liu Y, Seow HA, Ishiguro K, Baumann RP, Penketh PG, Shyam K, Akintujoye OM, Glazer PM, Sartorelli AC: Preclinical evaluation of Laromustine for use in combination with radiation therapy in the treatment of solid tumors. Int J Radiat Biol. 2012 Mar; 2011 Dec 20. PMID: 22111842
- Rogers FA, Lin SS, Hegan DC, Krause DS, Glazer PM: Targeted gene modification of hematopoietic progenitor cells in mice following systemic administration of a PNA-peptide conjugate. Mol Ther. 2012 Jan; 2011 Aug 9. PMID: 21829173
- Lin ZP, Lee Y, Lin F, Belcourt MF, Li P, Cory JG, Glazer PM, Sartorelli AC: Reduced level of ribonucleotide reductase R2 subunits increases dependence on homologous recombination repair of cisplatin-induced DNA damage. Mol Pharmacol. 2011 Dec; 2011 Aug 29. PMID: 21875941
- Babar IA, Czochor J, Steinmetz A, Weidhaas JB, Glazer PM, Slack FJ: Inhibition of hypoxia-induced miR-155 radiosensitizes hypoxic lung cancer cells. Cancer Biol Ther. 2011 Nov 15; 2011 Nov 15. PMID: 22027557
- Williams SA, Wilson JB, Clark AP, Mitson-Salazar A, Tomashevski A, Ananth S, Glazer PM, Semmes OJ, Bale AE, Jones NJ, Kupfer GM: Functional and physical interaction between the mismatch repair and FA-BRCA pathways. Hum Mol Genet. 2011 Nov 15; 2011 Aug 24. PMID: 21865299
- McNeer NA, Schleifman EB, Glazer PM, Saltzman WM: Polymer delivery systems for site-specific genome editing. J Control Release. 2011 Oct 30; 2011 May 18. PMID: 21620910
- Schleifman EB, Bindra R, Leif J, del Campo J, Rogers FA, Uchil P, Kutsch O, Shultz LD, Kumar P, Greiner DL, Glazer PM: Targeted disruption of the CCR5 gene in human hematopoietic stem cells stimulated by peptide nucleic acids. Chem Biol. 2011 Sep 23. PMID: 21944757
- Glazer PM, Le QT, Bristow R, Helleday T, Pelroy R, Bernhard EJ: New translational possibilities for microenvironmental modulation of radiosensitivity. Radiat Res. 2011 Sep; 2011 Jul 8. PMID: 21867431
- Glazer PM, Grandis J, Powell SN, Brown JM, Helleday T, Bristow R, Powis G, Hill RP, Le QT, Pelroy R, Mohla S, Bernhard EJ, NCI Workshop Participants.: Radiation Resistance in Cancer Therapy: meeting summary and research opportunities. Report of an NCI Workshop held September 1-3, 2010. Radiat Res. 2011 Sep; 2011 Jul 8. PMID: 21867428
- Lu Y, Chu A, Turker MS, Glazer PM: Hypoxia-induced epigenetic regulation and silencing of the BRCA1 promoter. Mol Cell Biol. 2011 Aug; 2011 Jun 13. PMID: 21670155
- Glazer PM, Grandis J, Powell SN, Brown JM, Helleday T, Bristow R, Powis G, Hill RP, Le QT, Pelroy R, Mohla S, Bernhard EJ: Radiation Resistance in Cancer Therapy: Meeting Summary and Research Opportunities: Report of an NCI Workshop held September 1-3, 2010. Radiat Res. 2011 Jul 8; 2011 Jul 8. PMID: 21740251
- McNeer NA, Chin JY, Schleifman EB, Fields RJ, Glazer PM, Saltzman WM: Nanoparticles deliver triplex-forming PNAs for site-specific genomic recombination in CD34+ human hematopoietic progenitors. Mol Ther. 2011 Jan; 2010 Sep 21. PMID: 20859257
- Klein TJ, Glazer PM: The tumor microenvironment and DNA repair. Semin Radiat Oncol. 2010 Oct. PMID: 20832021
- Hegan DC, Lu Y, Stachelek GC, Crosby ME, Bindra RS, Glazer PM: Inhibition of poly(ADP-ribose) polymerase down-regulates BRCA1 and RAD51 in a pathway mediated by E2F4 and p130. Proc Natl Acad Sci U S A. 2010 Feb 2; 2010 Jan 19. PMID: 20133863
- Rowe BP, Glazer PM: Emergence of rationally designed therapeutic strategies for breast cancer targeting DNA repair mechanisms. Breast Cancer Res. 2010; 2010 Apr 30. PMID: 20459590
- Stachelek GC, Dalal S, Donigan KA, Campisi Hegan D, Sweasy JB, Glazer PM: Potentiation of temozolomide cytotoxicity by inhibition of DNA polymerase beta is accentuated by BRCA2 mutation. Cancer Res. 2010 Jan 1; 2009 Dec 22. PMID: 20028873
- Lonkar P, Kim KH, Kuan JY, Chin JY, Rogers FA, Knauert MP, Kole R, Nielsen PE, Glazer PM: Targeted correction of a thalassemia-associated beta-globin mutation induced by pseudo-complementary peptide nucleic acids. Nucleic Acids Res. 2009 Jun; 2009 Apr 13. PMID: 19364810
- Kim Y, Lin Q, Glazer PM, Yun Z: Hypoxic tumor microenvironment and cancer cell differentiation. Curr Mol Med. 2009 May. PMID: 19519400
- Peterson-Roth E, Brdlik CM, Glazer PM: Src-Induced cisplatin resistance mediated by cell-to-cell communication. Cancer Res. 2009 Apr 15; 2009 Apr 7. PMID: 19351863
- Chin JY, Glazer PM: Repair of DNA lesions associated with triplex-forming oligonucleotides. Mol Carcinog. 2009 Apr. PMID: 19072762
- Crosby ME, Kulshreshtha R, Ivan M, Glazer PM: MicroRNA regulation of DNA repair gene expression in hypoxic stress. Cancer Res. 2009 Feb 1; 2009 Jan 13. PMID: 19141645
- Crosby ME, Devlin CM, Glazer PM, Calin GA, Ivan M: Emerging roles of microRNAs in the molecular responses to hypoxia. Curr Pharm Des. 2009. PMID: 19925433
- Chin JY, Kuan JY, Lonkar PS, Krause DS, Seidman MM, Peterson KR, Nielsen PE, Kole R, Glazer PM: Correction of a splice-site mutation in the beta-globin gene stimulated by triplex-forming peptide nucleic acids. Proc Natl Acad Sci U S A. 2008 Sep 9; 2008 Aug 29. PMID: 18757759
- Marek LR, Kottemann MC, Glazer PM, Bale AE: MEN1 and FANCD2 mediate distinct mechanisms of DNA crosslink repair. DNA Repair (Amst). 2008 Mar 1; 2008 Feb 6. PMID: 18258493
- Schleifman EB, Chin JY, Glazer PM: Triplex-mediated gene modification. Methods Mol Biol. 2008. PMID: 18370076
- Bindra RS, Glazer PM: Co-repression of mismatch repair gene expression by hypoxia in cancer cells: role of the Myc/Max network. Cancer Lett. 2007 Jul 8; 2007 Feb 1. PMID: 17275176
- Bindra RS, Crosby ME, Glazer PM: Regulation of DNA repair in hypoxic cancer cells. Cancer Metastasis Rev. 2007 Jun. PMID: 17415527
- Chin JY, Schleifman EB, Glazer PM: Repair and recombination induced by triple helix DNA. Front Biosci. 2007 May 1; 2007 May 1. PMID: 17485375
- Kim KH, Nielsen PE, Glazer PM: Site-directed gene mutation at mixed sequence targets by psoralen-conjugated pseudo-complementary peptide nucleic acids. Nucleic Acids Res. 2007; 2007 Oct 30. PMID: 17977869
- Gibson SL, Narayanan L, Hegan DC, Buermeyer AB, Liskay RM, Glazer PM: Overexpression of the DNA mismatch repair factor, PMS2, confers hypermutability and DNA damage tolerance. Cancer Lett. 2006 Dec 8; 2006 Jan 19. PMID: 16426742
- Hegan DC, Narayanan L, Jirik FR, Edelmann W, Liskay RM, Glazer PM: Differing patterns of genetic instability in mice deficient in the mismatch repair genes Pms2, Mlh1, Msh2, Msh3 and Msh6. Carcinogenesis. 2006 Dec; 2006 May 25. PMID: 16728433
- Bindra RS, Glazer PM: Basal repression of BRCA1 by multiple E2Fs and pocket proteins at adjacent E2F sites. Cancer Biol Ther. 2006 Oct; 2006 Oct 30. PMID: 17106239
- Gibson SL, Bindra RS, Glazer PM: CHK2-dependent phosphorylation of BRCA1 in hypoxia. Radiat Res. 2006 Oct. PMID: 17007555
- Knauert MP, Kalish JM, Hegan DC, Glazer PM: Triplex-stimulated intermolecular recombination at a single-copy genomic target. Mol Ther. 2006 Sep; 2006 May 30. PMID: 16731047
- Kim KH, Nielsen PE, Glazer PM: Site-specific gene modification by PNAs conjugated to psoralen. Biochemistry. 2006 Jan 10. PMID: 16388608
- Bindra RS, Gibson SL, Meng A, Westermark U, Jasin M, Pierce AJ, Bristow RG, Classon MK, Glazer PM: Hypoxia-induced down-regulation of BRCA1 expression by E2Fs. Cancer Res. 2005 Dec 15. PMID: 16357170
- Gibson SL, Bindra RS, Glazer PM: Hypoxia-induced phosphorylation of Chk2 in an ataxia telangiectasia mutated-dependent manner. Cancer Res. 2005 Dec 1. PMID: 16322218
- Kalish JM, Glazer PM: Targeted genome modification via triple helix formation. Ann N Y Acad Sci. 2005 Nov. PMID: 16394134
- Bindra RS, Schaffer PJ, Meng A, Woo J, Måseide K, Roth ME, Lizardi P, Hedley DW, Bristow RG, Glazer PM: Alterations in DNA repair gene expression under hypoxia: elucidating the mechanisms of hypoxia-induced genetic instability. Ann N Y Acad Sci. 2005 Nov. PMID: 16382054
- Rogers FA, Lloyd JA, Glazer PM: Triplex-forming oligonucleotides as potential tools for modulation of gene expression. Curr Med Chem Anticancer Agents. 2005 Jul. PMID: 16101484
- Kalish JM, Seidman MM, Weeks DL, Glazer PM: Triplex-induced recombination and repair in the pyrimidine motif. Nucleic Acids Res. 2005; 2005 Jun 16. PMID: 15961731
- Knauert MP, Lloyd JA, Rogers FA, Datta HJ, Bennett ML, Weeks DL, Glazer PM: Distance and affinity dependence of triplex-induced recombination. Biochemistry. 2005 Mar 15. PMID: 15751961
- Bindra RS, Glazer PM: Genetic instability and the tumor microenvironment: towards the concept of microenvironment-induced mutagenesis. Mutat Res. 2005 Jan 6. PMID: 15603753
- Rogers FA, Manoharan M, Rabinovitch P, Ward DC, Glazer PM: Peptide conjugates for chromosomal gene targeting by triplex-forming oligonucleotides. Nucleic Acids Res. 2004; 2004 Dec 15. PMID: 15602001
- Bindra RS, Schaffer PJ, Meng A, Woo J, Måseide K, Roth ME, Lizardi P, Hedley DW, Bristow RG, Glazer PM: Down-regulation of Rad51 and decreased homologous recombination in hypoxic cancer cells. Mol Cell Biol. 2004 Oct. PMID: 15367671
- Jensen R, Glazer PM: Cell-interdependent cisplatin killing by Ku/DNA-dependent protein kinase signaling transduced through gap junctions. Proc Natl Acad Sci U S A. 2004 Apr 20; 2004 Apr 6. PMID: 15069205
- Kuan JY, Glazer PM: Targeted gene modification using triplex-forming oligonucleotides. Methods Mol Biol. 2004. PMID: 14769962
- Haffty BG, Glazer PM: Molecular markers in clinical radiation oncology. Oncogene. 2003 Sep 1. PMID: 12947398
- Seidman MM, Glazer PM: The potential for gene repair via triple helix formation. J Clin Invest. 2003 Aug. PMID: 12925687
- Mihaylova VT, Bindra RS, Yuan J, Campisi D, Narayanan L, Jensen R, Giordano F, Johnson RS, Rockwell S, Glazer PM: Decreased expression of the DNA mismatch repair gene Mlh1 under hypoxic stress in mammalian cells. Mol Cell Biol. 2003 May. PMID: 12697826
- Macris MA, Glazer PM: Transcription dependence of chromosomal gene targeting by triplex-forming oligonucleotides. J Biol Chem. 2003 Jan 31; 2002 Nov 12. PMID: 12431993
- Rogers FA, Vasquez KM, Egholm M, Glazer PM: Site-directed recombination via bifunctional PNA-DNA conjugates. Proc Natl Acad Sci U S A. 2002 Dec 24; 2002 Dec 2. PMID: 12461167
- Peretz S, Kim C, Rockwell S, Baserga R, Glazer PM: IGF1 receptor expression protects against microenvironmental stress found in the solid tumor. Radiat Res. 2002 Aug. PMID: 12105987
- Haffty BG, Harrold E, Khan AJ, Pathare P, Smith TE, Turner BC, Glazer PM, Ward B, Carter D, Matloff E, Bale AE, Alvarez-Franco M: Outcome of conservatively managed early-onset breast cancer by BRCA1/2 status. Lancet. 2002 Apr 27. PMID: 11988246