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Your Environment. Your Health.

ENVIRONMENTAL CARCINOGEN-DNA ADDUCTS: NER RECOGNITION

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Principal Investigator: Broyde, Suse
Institute Receiving Award New York University
Location New York, NY
Grant Number R01ES025987
Funding Organization National Institute of Environmental Health Sciences
Award Funding Period 01 Jun 2016 to 31 May 2022
DESCRIPTION (provided by applicant):  : The human genome is under constant attack from environmental pollutants, endogenous reactive oxidizing species that are secreted in human tissues during the inflammatory response, and ultraviolet components of sunlight. Among the exogenous cancer-causing environmental contaminants are polycyclic aromatic compounds that are byproducts of fossil fuel combustion found at toxic waste dumps and superfund sites, in airborne particulates, and in our food and water. The DNA lesions derived from polycyclic aromatic compounds, inflammation-related reactive oxidizing species, and ultraviolet light result in the accumulation of malignant mutations that lead to a variety of human cancers. However, not all DNA lesions are equally effective in promoting human diseases: while lesions can be excised by the human nucleotide excision repair (NER) mechanism, some DNA lesions are rapidly repaired, some are repaired slowly, and some are entirely resistant to NER and are therefore particularly genotoxic. The vital importance of NER is demonstrated in the devastating human disorder xeroderma pigmentosum, caused by mutations in various NER genes. However, why certain DNA lesions are NER-resistant and others are not when NER is normal, is not understood. The objective of this project is to provide mechanistic insights into this puzzling variability of DNA lesion repair, by focusing on the key step of lesion recognition in NER, to yield a molecular understanding of NER resistance. We hypothesize that how well a lesion is recognized is determined by the extent of destabilization or stabilization that it impose on DNA: stabilization leads to repair resistance and destabilization facilitates repair. We will dissect the structural, dynamic and thermodynamic properties for a selected set of DNA lesions that govern whether they are recognized by Rad4-Rad23, the yeast ortholog of the human XPC-RAD23B lesion recognition factor. In Aim 1 we will determine the extent that local thermodynamic stability of lesion-containing DNA regulates their recognition. In Aim 2 we will determine the molecular mechanism for productive binding of Rad4-Rad23 that successfully recognizes the lesions and correctly recruits subsequent NER factors, and how the binding pathway and free energies along this pathway depend on lesion structures. In Aim 3 we will investigate DNA complexed with histone proteins in nucleosomes, the fundamental packaging unit of DNA in cells. We will determine how access of the NER proteins to DNA lesions in nucleosomes is governed by the lesion's structural and dynamic properties to promote or inhibit repair. The novel insights into the DNA lesion recognition mechanisms of NER that we will gain may lead to the development of more effective, less NER- susceptible chemotherapeutic agents, since the efficacy of current drugs is impaired by NER. Furthermore, such understanding will help to identify the most genotoxic cancer-causing precursors among the many environmental contaminants, thus allowing for the development of better targeted abatement policies and biomonitoring methods of the associated health risks.
Science Code(s)/Area of Science(s) Primary: 09 - Genome Integrity
Publications See publications associated with this Grant.
Program Officer Michelle Heacock
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