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Douglas E Brash, PhD

Senior Research Scientist in Therapeutic Radiology and in Dermatology and Clinical Professor of Therapeutic Radiology

Contact Information

Douglas E Brash, PhD

Lab Location

Office Location

Mailing Address

  • Therapeutic Radiology

    PO Box 208040

    New Haven, CT 06520-8040

    United States

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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

Clinical Trials

Study Title
Molecular Markers of UV Exposure and Cancer Risk in Skin
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