Chemistry and Biology of Oxidized Purine Lesions in DNA

$266,919R01FY2014CANIH

University Of Utah, Salt Lake City UT

Investigators

Cynthia J. Burrowscontact Sheila Sue David

Linked publications, trials & patents

Paper 37034403 Paper 36813885 Paper 36037088 Paper 34747670 Paper 33929180 Paper 32785348 Paper 32716425 Paper 32567845 Paper 32284409 Paper 32109332 Paper 32069022 Paper 31880930 Paper 31733589 Paper 31241930 Paper 30916339 Paper 30821442 Paper 30604962 Paper 30198001 Paper 30063821 Paper 29718661 Paper 29694860 Paper 29320161 Paper 28936535 Paper 28829124 Paper 28645369 Paper 28629775 Paper 28150947 Paper 28143930 Paper 27880870 Paper 27737553 Paper 26686913 Paper 26582419 Paper 26405692 Paper 26313343 Paper 26117536 Paper 26097262 Paper 26092110 Paper 25853314 Paper 25813041 Paper 25539403 Paper 25016526 Paper 24649945 Paper 24563606 Paper 24215588 Paper 23930966 Paper 23926102 Paper 23755964 Paper 23438298 Paper 23106240 Paper 22880947 Paper 22639086 Paper 22175854 Paper 22065741 Paper 21689934 Paper 21516189 Paper 21445431 Paper 21068368 Paper 20955798 Paper 20458355 Paper 20185759 Paper 20166752 Paper 20099873 Paper 19805252 Paper 19217358 Paper 19146379 Paper 18543945 Paper 18154319 Paper 17655276 Paper 17627905 Paper 17581577 Paper 17323928 Paper 16497015 Paper 14611206 Paper 14596616 Paper 14503888 Paper 12899611 Paper 12426118

Abstract

DESCRIPTION (provided by applicant): A causative role has been established between compromised DNA repair and the development of human cancers. DNA bases are subject to oxidative stress undergoing chemical modification of guanine and other bases as a result of endogenous oxidants, inflammatory responses to infection and injury, and exposure to redox-active environmental toxins. While much attention has been focused on G to T mutations as a result of the oxidized guanine lesion 8-oxoguanine (OG), this project investigates the hyperoxidized guanine lesions resulting from further oxidation of OG. These lesions constitute a family of highly mutagenic hydantoin structures including spiroiminodihydantoin (Sp) and guanidinohydantoin (Gh) that appear to cause G to C in addition to G to T mutations. In the present work, related members of this class of compounds will be studied to further explore the relationship between oxidation pathway, product structure, and activity with DNA processing enzymes including base excision repair and nucleotide excision repair mechanisms. The new structures to be studied include amine adducts of oxidized guanosine. Novel pathways are proposed that might explain additional observations in the mutagenic spectrum of oxidative stress, including the formation of double-stranded tandem lesions. The specific aims of this work are to: (1) resolve structural questions surrounding the formation of hydantoin lesions in duplex DNA through the use of synthetic lesion-containing oligodeoxynucleotides, mass spectrometry, and x-ray crystallography, (2) understand the roles of base excision repair vs. nucleotide excision repair for hydantoin lesions via in vitro and in vivo biochemical assays with a particular focus on the role of the Nei-like (hNEIL1) and Fpg glycosylases, and (3) develop innovative assays to detect hydantoin products in cell lysates by generating aptamers to DNA lesions coupled to fluorescent readouts.

View original record on NIH RePORTER →