Research & Publications
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) Exploring how UVB-induced apoptosis and UV-driven cell fate decisions drive a single mutant cell to clonally expand. 2) Determining rates of DNA photoproduct formation and repair across the genome, as dosimeters of a person's past UV exposure. 3) The interaction of UV and melanin in causing melanoma.
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 rather than 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.
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