R01ES032814

Genome-Wide Analysis of the Formation and Mutagenesis of Atypical UV Photoproducts in Skin Cancer - Abstract:

Exposure to solar ultraviolet (UV) light creates DNA damage that induces high levels of somatic mutations in human skin cancers like melanoma. UV light most commonly causes cyclobutane pyrimidine dimers (CPDs) and 6-4 photoproducts (6-4PPs) at dipyrimidine sequences (i.e., TT, TC, CT, and CC). Deamination of cytidines in these lesions or mutagenic bypass leads to their frequent conversion to mutations. As a result, UV-exposed cells and skin cancers are dominated by C to T and CC to TT substitutions in dipyrimidine sequences that collectively constitute a UV mutation signature.

Surprisingly, many driver mutations that contribute to melanoma progression have sequence context and substitution characteristics that do not conform to the canonical UV mutation signature. For example, the most common melanoma driver mutation, BRAF V600E, involves a T to A substitution in a GTG sequence context. This difference in mutation characteristics between most UV-induced mutations and melanoma driver mutations has led to the hypothesis that UV light induces melanomagenesis by mechanisms other than the induction of mutations.

However, we have recently provided experimental evidence of mutations caused by rare, non-canonical UV lesions in whole genome sequenced yeast and bioinformatics evidence of similar lesions in human clinical skin cancers. These lesions are likely bulky photoproducts formed at TA, CA, and AC dinucleotides. Strikingly, the mutations associated with these atypical UV photoproducts have identical characteristics to many recurrent driver mutations in melanoma, suggesting that these rare lesions may play a significant role in causing skin cancer.

The objective of this proposal is to better define the characteristics of atypical UV photoproducts and their contribution to cancer progression.

In Aim I, we will utilize CPD and 6-4PP photolyases expressed in yeast to assign UV-induced mutation classes to their corresponding lesion types, as well as assess the ability of physiological UVB light to induce mutation classes associated with atypical UV photoproducts in yeast and human cells.

In Aim II, we will analyze the genome-wide distribution of atypical TA photoproducts using a novel high-throughput sequencing method, called UVDE-SEQ. We will also characterize the formation of putative CA and AC photoproducts and their contribution to oncogenic BRAF mutations.

Finally, Aim III will identify DNA polymerases involved in the error-free and error-prone bypass of TA and AC photoproducts.

Successful completion of these aims will provide new insights into the molecular causes of skin cancer and thereby define a new paradigm of UV mutagenesis that could potentially explain the epidemiological association of acute UV exposure with increased melanoma incidence.

University Of Vermont & State Agricultural College

<P>THE GOALS ARE:</P><UL><LI>TO FOSTER FUNDAMENTAL CREATIVE DISCOVERIES, INNOVATIVE RESEARCH STRATEGIES, AND THEIR APPLICATIONS AS A BASIS FOR ULTIMATELY PROTECTING AND IMPROVING HEALTH;</LI><LI>TO DEVELOP, MAINTAIN, AND RENEW SCIENTIFIC HUMAN AND PHYSICAL RESOURCES THAT WILL ENSURE THE NATION'S CAPABILITY TO PREVENT DISEASE;</LI><LI>TO EXPAND THE KNOWLEDGE BASE IN MEDICAL AND ASSOCIATED SCIENCES IN ORDER TO ENHANCE THE NATION'S ECONOMIC WELL-BEING AND ENSURE A CONTINUED HIGH RETURN ON THE PUBLIC INVESTMENT IN RESEARCH; AND</LI><LI>TO EXEMPLIFY AND PROMOTE THE HIGHEST LEVEL OF SCIENTIFIC INTEGRITY, PUBLIC ACCOUNTABILITY, AND SOCIAL RESPONSIBILITY IN THE CONDUCT OF SCIENCE.</LI></UL><P>IN REALIZING THESE GOALS, THE NIH PROVIDES LEADERSHIP AND DIRECTION TO PROGRAMS DESIGNED TO IMPROVE THE HEALTH OF THE NATION BY CONDUCTING AND SUPPORTING RESEARCH:</P><UL><LI>IN THE CAUSES, DIAGNOSIS, PREVENTION, AND CURE OF HUMAN DISEASES;</LI><LI>IN THE PROCESSES OF HUMAN GROWTH AND DEVELOPMENT;</LI><LI>IN THE BIOLOGICAL EFFECTS OF ENVIRONMENTAL CONTAMINANTS;</LI><LI>IN THE UNDERSTANDING OF MENTAL, ADDICTIVE AND PHYSICAL DISORDERS; AND</LI><LI>IN DIRECTING PROGRAMS FOR THE COLLECTION, DISSEMINATION, AND EXCHANGE OF INFORMATION IN MEDICINE AND HEALTH, INCLUDING THE DEVELOPMENT AND SUPPORT OF MEDICAL LIBRARIES AND THE TRAINING OF MEDICAL LIBRARIANS AND OTHER HEALTH INFORMATION SPECIALISTS.</LI></UL>

93.113 - Environmental Health

National Institute of Environmental Health Sciences (NIEHS) [HHS - NIH]

Burlington, Vermont 054051704 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-25-301)

Amendment Since initial award the End Date has been extended from 01/31/26 to 06/19/30 and the total obligations have increased 1295% from $416,865 to $5,815,820.