Douglas E Brash, PhD
Senior Research Scientist in Therapeutic Radiology and in Dermatology and Clinical Professor of Therapeutic Radiology
Research & Publications
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Research Summary
Cancer begins as an encounter between a carcinogen and a gene. We are pinpointing these early events, which occur decades before the appearance of a tumor. Our past work on sunlight-induced mutations in tumor suppressor genes has led us to three current topics: 1) The interaction of UV and melanin in causing melanoma. 2) Determining rates of DNA UV-photoproduct formation and repair across the genome, as dosimeters of a person's past UV exposure. 3) Using photoproduct and mutation data from a person's normal skin to predict individual skin cancer risk and need for monitoring – precision prevention.
Extensive Research Description
The story thus far, from photons up to cells: UV leads to mutations at the site of DNA photoproducts (rather than elevating genomic instability); the important photoproducts are cyclobutane pyrimidine dimers (CPDs) and (6-4) photoproducts, which join adjacent cytosines or thymines; only the cytosine mutates; these unique properties create a characteristic "mutation signature" for UV that can be seen in tumors decades later; sunlight mutates the P53 and PTCH genes in non-melanoma skin cancer; P53 is required for UV-induced apoptosis, which prevents mutations; apoptosis is signaled by DNA photoproducts in actively transcribed genes and by a product of UV-irradiated melanin; another cause of apoptosis is exposure of melanin to sunlight, particularly the melanin found in blonde and red hair; and our sun-exposed skin carries about 60,000 tiny clones of P53-mutant keratinocytes. Expansion of single mutant cells into clones is due to physiology, not a 2nd mutation: UV-induced apoptosis deletes normal progenitor cells while sparing the mutant ones. UV also tilts the progenitor cell's fate decision toward self-renewal rather than differentiation. Recently, we found two novel properties of CPDs: They can also be created in the dark by a novel physical chemistry process termed "chemiexcitation" that excites electrons in the skin pigment melanin, after which the energy transfers to DNA. They occur 100-fold more frequently at specific sites in the DNA that we term "hyperhotspots". Now, the lab is in the midst of some practical applications:
- Using UV-sensitive DNA targets, for CPDs and mutations, to determine an individual's past UV exposure and predict future skin cancer risk. Early detection in at-risk individuals can lead to survival rates approaching 100%.
- Blocking chemiexcitation as an "after-sun" approach to preventing skin cancer.
- Determining whether chemiexcitation also happens during wound healing and in diseases such as Parkinson's.
Coauthors
Research Interests
DNA Damage; DNA Repair; Melanoma, Experimental; Molecular Biology; Skin Neoplasms; Sunburn; Sunlight; Sunscreening Agents; Ultraviolet Rays; Xeroderma Pigmentosum; Mutagenesis; Photobiology; DNA Adducts
Public Health Interests
Cancer
Research Image
p53-mutant clone in normal tissue.
Clone of p53-mutated keratinocytes in a 3D confocal image of an epidermal whole-mount of normal human skin.
Selected Publications
- Reply to Pfeffer: Macular degeneration clues from comparative anatomyWang K, Lyu Y, Tschulakow A, Brash D, Schraermeyer U. Reply to Pfeffer: Macular degeneration clues from comparative anatomy. Proceedings Of The National Academy Of Sciences Of The United States Of America 2023, 120: e2315582120. PMID: 37871227, PMCID: PMC10622899, DOI: 10.1073/pnas.2315582120.
- Next-generation sequencing methodologies to detect low-frequency mutations: “Catch me if you can”Menon V, Brash D. Next-generation sequencing methodologies to detect low-frequency mutations: “Catch me if you can”. Mutation Research/Reviews In Mutation Research 2023, 792: 108471. PMID: 37716438, DOI: 10.1016/j.mrrev.2023.108471.
- Chemiexcitation and melanin in photoreceptor disc turnover and prevention of macular degenerationLyu Y, Tschulakow A, Wang K, Brash D, Schraermeyer U. Chemiexcitation and melanin in photoreceptor disc turnover and prevention of macular degeneration. Proceedings Of The National Academy Of Sciences Of The United States Of America 2023, 120: e2216935120. PMID: 37155898, PMCID: PMC10194005, DOI: 10.1073/pnas.2216935120.
- Chemiexcited Neurotransmitters and Hormones Create DNA Photoproducts in the DarkGonçalves L, Angelé-Martínez C, Premi S, Palmatier M, Prado F, Di Mascio P, Bastos E, Brash D. Chemiexcited Neurotransmitters and Hormones Create DNA Photoproducts in the Dark. ACS Chemical Biology 2023, 18: 484-493. PMID: 36775999, PMCID: PMC10276651, DOI: 10.1021/acschembio.2c00787.
- Chemiexcitation: Mammalian Photochemistry in the Dark†Brash D, Goncalves L. Chemiexcitation: Mammalian Photochemistry in the Dark†. Photochemistry And Photobiology 2023, 99: 251-276. PMID: 36681894, PMCID: PMC10065968, DOI: 10.1111/php.13781.
- Carcinogenesis: UV RadiationBrash D, Heffernan T, Nghiem P, Cho R. Carcinogenesis: UV Radiation. 2016, 887-902. DOI: 10.1007/978-3-662-47398-6_56.
- Carcinogenesis: UV RadiationBrash D, Heffernan T, Nghiem P, Cho R. Carcinogenesis: UV Radiation. 2015, 1-17. DOI: 10.1007/978-3-642-27814-3_56-2.
- Carcinogenesis: UV Radiation*Brash D, Heffernan T, Nghiem P. Carcinogenesis: UV Radiation*. 2010, 567-578. DOI: 10.1007/978-3-540-89656-2_56.
- Reply: Lymphomagenesis and female-specific lethality in p53-deficient mice occur independently of E2f1Brash D. Reply: Lymphomagenesis and female-specific lethality in p53-deficient mice occur independently of E2f1. Nature Cell Biology 2004, 6: 567-568. DOI: 10.1038/ncb0704-567.
- Escaping the stem cell compartment: Sustained UVB exposure allows p53-mutant keratinocytes to colonize adjacent epidermal proliferating units without incurring additional mutationsZhang W, Remenyik E, Zelterman D, Brash D, Wikonkal N. Escaping the stem cell compartment: Sustained UVB exposure allows p53-mutant keratinocytes to colonize adjacent epidermal proliferating units without incurring additional mutations. Proceedings Of The National Academy Of Sciences Of The United States Of America 2001, 98: 13948-13953. PMID: 11707578, PMCID: PMC61147, DOI: 10.1073/pnas.241353198.
- The DNA Damage Signal for Mdm2 Regulation, Trp53 Induction, and Sunburn Cell Formation In Vivo Originates from Actively Transcribed GenesBrash D, Wikonkal N, Remenyik E, van der Horst G, Friedberg E, Cheo D, van Steeg H, Westerman A, van Kranen H. The DNA Damage Signal for Mdm2 Regulation, Trp53 Induction, and Sunburn Cell Formation In Vivo Originates from Actively Transcribed Genes. Journal Of Investigative Dermatology 2001, 117: 1234-1240. PMID: 11710938, DOI: 10.1046/j.0022-202x.2001.01554.x.
- Transgenic expression of survivin in keratinocytes counteracts UVB-induced apoptosis and cooperates with loss of p53Grossman D, Kim P, Blanc-Brude O, Brash D, Tognin S, Marchisio P, Altieri D. Transgenic expression of survivin in keratinocytes counteracts UVB-induced apoptosis and cooperates with loss of p53. Journal Of Clinical Investigation 2001, 108: 991-999. PMID: 11581300, PMCID: PMC200956, DOI: 10.1172/jci13345.
- Regulation of TNFα production and release in human and mouse keratinocytes and mouse skin after UV‐B irradiationYarosh D, Both D, Kibitel J, Anderson C, Elmets C, Brash D, Brown D. Regulation of TNFα production and release in human and mouse keratinocytes and mouse skin after UV‐B irradiation. Photodermatology Photoimmunology & Photomedicine 2000, 16: 263-270. PMID: 11132130, DOI: 10.1034/j.1600-0781.2000.160606.x.
- Induction of cyclin-dependent kinase inhibitors and G 1 prolongation by the chemopreventive agent N -acetylcysteineLiu M, Wikonkal N, Brash D. Induction of cyclin-dependent kinase inhibitors and G 1 prolongation by the chemopreventive agent N -acetylcysteine. Carcinogenesis 1999, 20: 1869-1872. PMID: 10469636, DOI: 10.1093/carcin/20.9.1869.
- Ultraviolet Radiation Induced Signature Mutations in PhotocarcinogenesisWikonkal N, Brash D. Ultraviolet Radiation Induced Signature Mutations in Photocarcinogenesis. Journal Of Investigative Dermatology Symposium Proceedings 1999, 4: 6-10. PMID: 10537000, DOI: 10.1038/sj.jidsp.5640173.
- UV Induces p21WAF1/CIP1 Protein in Keratinocytes Without p53Liu M, Wikonkal N, Brash D. UV Induces p21WAF1/CIP1 Protein in Keratinocytes Without p53. Journal Of Investigative Dermatology 1999, 113: 283-284. PMID: 10469320, DOI: 10.1046/j.1523-1747.1999.00657.x.
- Tumor necrosis factor-α gene expression is induced by cyclobutyl pyrimidine dimers in DNAYarosh D, Klein J, O'Connor A, Kibitel J, Brash D, Hejmadi V, Sutherland B. Tumor necrosis factor-α gene expression is induced by cyclobutyl pyrimidine dimers in DNA. Journal Of Dermatological Science 1998, 16: s177. DOI: 10.1016/s0923-1811(98)84055-3.
- Sunlight and the onset of skin cancerBrash D. Sunlight and the onset of skin cancer. Trends In Genetics 1997, 13: 410-414. PMID: 9351343, DOI: 10.1016/s0168-9525(97)01246-8.
- Frequent clones of p53-mutated keratinocytes in normal human skinJonason A, Kunala S, Price G, Restifo R, Spinelli H, Persing J, Leffell D, Tarone R, Brash D. Frequent clones of p53-mutated keratinocytes in normal human skin. Proceedings Of The National Academy Of Sciences Of The United States Of America 1996, 93: 14025-14029. PMID: 8943054, PMCID: PMC19488, DOI: 10.1073/pnas.93.24.14025.
- The role of the human homologue of Drosophila patched in sporadic basal cell carcinomasGailani M, Ståhle-Bäckdahl M, Leffell D, Glyn M, Zaphiropoulos P, Undén A, Dean M, Brash D, Bale A, Toftgård R. The role of the human homologue of Drosophila patched in sporadic basal cell carcinomas. Nature Genetics 1996, 14: 78-81. PMID: 8782823, DOI: 10.1038/ng0996-78.
- Cellular proofreadingBrash D. Cellular proofreading. Nature Medicine 1996, 2: 525-526. PMID: 8616708, DOI: 10.1038/nm0596-525.
- Relationship Between Sunlight Exposure and a Key Genetic Alteration in Basal Cell CarcinomaGailani M, Leffell D, Ziegler A, Gross E, Brash D, Bale A. Relationship Between Sunlight Exposure and a Key Genetic Alteration in Basal Cell Carcinoma. Journal Of The National Cancer Institute 1996, 88: 349-354. PMID: 8609643, DOI: 10.1093/jnci/88.6.349.
- Wrinkles waiting for GOD0TBrash D, Gilchrest B. Wrinkles waiting for GOD0T. Nature 1996, 379: 301-302. PMID: 8552182, DOI: 10.1038/379301a0.
- What Is Excellence?Brash D. What Is Excellence? Science 1995, 270: 1556-1557. DOI: 10.1126/science.270.5242.1556-b.
- Intragenic Domains of Strand-specific Repair inEscherichia coliKunala S, Brash D. Intragenic Domains of Strand-specific Repair inEscherichia coli. Journal Of Molecular Biology 1995, 246: 264-272. PMID: 7869378, DOI: 10.1006/jmbi.1994.0082.
- Sunburn and p53 in the onset of skin cancerZiegler A, Jonason A, Leffellt D, Simon J, Sharma H, Kimmelman J, Remington L, Jacks T, Brash D. Sunburn and p53 in the onset of skin cancer. Nature 1994, 372: 773-776. PMID: 7997263, DOI: 10.1038/372773a0.
- Local recurrence versus new primary: Clinical analysis of 82 breast relapses and potential applications for genetic fingerprintingHaffty B, Carter D, Flynn S, Fischer D, Brash D, Simons J, Ziegler A, Fischer J. Local recurrence versus new primary: Clinical analysis of 82 breast relapses and potential applications for genetic fingerprinting. International Journal Of Radiation Oncology • Biology • Physics 1993, 27: 575-583. PMID: 8226151, DOI: 10.1016/0360-3016(93)90382-6.
- Infectious paradigmBRASH D. Infectious paradigm. Nature 1991, 351: 9-9. PMID: 2027389, DOI: 10.1038/351009c0.
- Ultraviolet Mutagenesis of a Shuttle Vector Plasmid in Repair Proficient and Deficient Human CellsSeidman M, Brash D, Settharam S, Kraemer K, Bredberg A. Ultraviolet Mutagenesis of a Shuttle Vector Plasmid in Repair Proficient and Deficient Human Cells. 1991, 183-192. DOI: 10.1007/978-1-4615-3732-8_23.
- Rapid repair kinetics of pyrimidine(6–4)pyrimidone photoproducts in human cells are due to excision rather than conformational changeMitchell D, Brash D, Nairn R. Rapid repair kinetics of pyrimidine(6–4)pyrimidone photoproducts in human cells are due to excision rather than conformational change. Nucleic Acids Research 1990, 18: 963-971. PMID: 2315046, PMCID: PMC330351, DOI: 10.1093/nar/18.4.963.
- Defective DNA Repair in Humans: Clinical and Molecular Studies of Xeroderma PigmentosumKraemer K, Seetharam S, Seidman M, Bredberg A, Brash D, Waters H, Protić-Sablijć M, Peck G, DiGiovanna J, Moshell A, Tarone R, Jones G, Parshad R, Sanford K. Defective DNA Repair in Humans: Clinical and Molecular Studies of Xeroderma Pigmentosum. 1990, 95-104. DOI: 10.1007/978-1-4613-0637-5_7.
- Ultraviolet photoproducts at the ochre suppressor mutation site in the gln U gene of Escherichia coli: Relevance to “mutation frequency decline”Garvey N, Witkin E, Brash D. Ultraviolet photoproducts at the ochre suppressor mutation site in the gln U gene of Escherichia coli: Relevance to “mutation frequency decline”. Molecular Genetics And Genomics 1989, 219: 359-364. PMID: 2695824, DOI: 10.1007/bf00259607.
- Molecular Studies of Mutagenesis using Plasmid Vectors in Xeroderma Pigmentosum CellsKraemer K, Seetharam S, Brash D, Bredberg A, Protic’-Sabljic’ M, Seidman M. Molecular Studies of Mutagenesis using Plasmid Vectors in Xeroderma Pigmentosum Cells. 1989, 183-193. DOI: 10.1007/978-1-4684-1327-4_17.
- UV MUTAGENIC PHOTOPRODUCTS IN Escherichia coli AND HUMAN CELLS: A MOLECULAR GENETICS PERSPECTIVE ON HUMAN SKIN CANCER*Brash D. UV MUTAGENIC PHOTOPRODUCTS IN Escherichia coli AND HUMAN CELLS: A MOLECULAR GENETICS PERSPECTIVE ON HUMAN SKIN CANCER*. Photochemistry And Photobiology 1988, 48: 59-66. PMID: 3064116, DOI: 10.1111/j.1751-1097.1988.tb02786.x.
- Overview of human cells in genetic research: Altered phenotypes in human cells caused by transferred genesBrash D, Mark G, Farrell M, Harris C. Overview of human cells in genetic research: Altered phenotypes in human cells caused by transferred genes. Somatic Cell And Molecular Genetics 1987, 13: 429-440. PMID: 3331832, DOI: 10.1007/bf01534944.
- Strontium Phosphate Transfection of Human Cells in Primary Culture: Stable Expression of the Simian Virus 40 Large-T-Antigen Gene in Primary Human Bronchial Epithelial CellsBrash D, Reddel R, Quanrud M, Yang K, Farrell M, Harris C. Strontium Phosphate Transfection of Human Cells in Primary Culture: Stable Expression of the Simian Virus 40 Large-T-Antigen Gene in Primary Human Bronchial Epithelial Cells. Molecular And Cellular Biology 1987, 7: 2031-2034. DOI: 10.1128/mcb.7.5.2031-2034.1987.
- Strontium Phosphate Transfection of Human Cells in Primary Culture: Stable Expression of the Simian Virus 40 Large-T-Antigen Gene in Primary Human Bronchial Epithelial CellsBrash D, Reddel R, Quanrud M, Yang K, Farrell M, Harris C. Strontium Phosphate Transfection of Human Cells in Primary Culture: Stable Expression of the Simian Virus 40 Large-T-Antigen Gene in Primary Human Bronchial Epithelial Cells. Molecular And Cellular Biology 1987, 7: 2031-2034. DOI: 10.1128/mcb.7.5.2031-2034.1987.
- Substrate range of the 40,000-dalton DNA-photoreactivating enzyme from Escherichia coli.Sutherland B, Oliveira O, Ciarrocchi G, Brash D, Haseltine W, Lewis R, Hanawalt P. Substrate range of the 40,000-dalton DNA-photoreactivating enzyme from Escherichia coli. Biochemistry 1986, 25: 681-7. PMID: 3513832, DOI: 10.1021/bi00351a026.
- Longevity-dependent organ-specific accumulation of DNA damage in two closely related murine speciesSu C, Brash D, Turturro A, Hart R. Longevity-dependent organ-specific accumulation of DNA damage in two closely related murine species. Mechanisms Of Ageing And Development 1984, 27: 239-247. PMID: 6492898, DOI: 10.1016/0047-6374(84)90049-6.
- Target Organ Specificity: Diethylnitrosamine-and Dibenzylnitrosamine-induced Single-strand Breaks Plus Alkali-labile BondsBrash D, Su C, Nabi H, Reuter K, Ortman J, Sheikh Y, Hart R. Target Organ Specificity: Diethylnitrosamine-and Dibenzylnitrosamine-induced Single-strand Breaks Plus Alkali-labile Bonds. International Journal Of Toxicology 1984, 3: 207-216. DOI: 10.3109/10915818409018034.
- UV-induced mutation hotspots occur at DNA damage hotspotsBrash D, Haseltine W. UV-induced mutation hotspots occur at DNA damage hotspots. Nature 1982, 298: 189-192. PMID: 7045692, DOI: 10.1038/298189a0.
- DNA repair assays as tests for environmental mutagens A report of the U.S. EPA gene-tox programLarsen K, Brash D, Cleaver J, Hart R, Maher V, Painter R, Sega G. DNA repair assays as tests for environmental mutagens A report of the U.S. EPA gene-tox program. Mutation Research/Fundamental And Molecular Mechanisms Of Mutagenesis 1982, 98: 287-318. PMID: 7050696, DOI: 10.1016/0165-1110(82)90037-9.
- Determination of DNA superhelicity and extremely low levels of DNA strand breaks in low numbers of nonradiolabeled cells by DNA-4′,6-diamidino-2-phenylindole fluorescence in nucleoid gradientsLipetz P, Brash D, Joseph L, Jewett H, Lisle D, Lantry L, Hart R, Stephens R. Determination of DNA superhelicity and extremely low levels of DNA strand breaks in low numbers of nonradiolabeled cells by DNA-4′,6-diamidino-2-phenylindole fluorescence in nucleoid gradients. Analytical Biochemistry 1982, 121: 339-348. PMID: 7103066, DOI: 10.1016/0003-2697(82)90491-2.
- New Approaches to DNA Damage and Repair: The Ultraviolet Light ExampleHaseltine W, Gordon L, Lindan C, Lippke J, Brash D, Lo K, Royer-Pokora B. New Approaches to DNA Damage and Repair: The Ultraviolet Light Example. 1982, 315-332. DOI: 10.1007/978-1-4613-3476-7_21.
- Role of gene expression in mechanisms of toxicity/carcinogenicity relative to environmental cancer, heart, and lung diseaseBrash D. Role of gene expression in mechanisms of toxicity/carcinogenicity relative to environmental cancer, heart, and lung disease. Journal Of Environmental Science And Health Part A 1982, 17: 589-598. DOI: 10.1080/10934528209375061.
- Molecular Biology of AgingBrash D, Hart R. Molecular Biology of Aging. 1978, 57-81. DOI: 10.1007/978-1-4613-3994-6_4.