The genes of all cells are continuously damaged by extrinsic agents such as radiation and chemicals as well as endogenous, spontaneous processes. DMA damage, if left unrepaired, can result in a number of deleterious biological consequences, including the production of mutant proteins that can change the cellular phenotype. Delineating the processes that generate mutant proteins is of great importance for our understanding of the endpoints of genetic damage which include cell death, changes in physiology and, in the case of mammalian cells, tumor development. The vast majorities of DNA damage-induced mutagenesis studies are replication-centric and are based on models of DNA polymerase errors occurring in the vicinity of the lesion. Few studies have addressed the possibility that mutagenesis at the level of transcription (via RNA polymerase encounters with DNA damage) may also be an important pathway for generating mutant proteins, particularly in non-dividing cells. The studies proposed in this project are focused on two major areas: (i) the delineation of the roles that DNA repair excision pathways (in bacterial and mammalian cells) play in transcriptional mutagenesis (TM), and (ii) whether TM can activate a mutant Ras oncogene-mediated signaling pathway related to mammalian tumor development. These studies should substantially increase our understanding of the occurrence and biological relevance of TM as well as provide important insights into the DNA repair systems employed by bacterial and mammalian cells for reversing frequently occurring and ionizing radiation-induced DNA base damages under both growth and non-growth conditions.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA120288-05
Application #
8107849
Study Section
Radiation Therapeutics and Biology Study Section (RTB)
Program Officer
Okano, Paul
Project Start
2007-09-01
Project End
2014-05-31
Budget Start
2011-08-01
Budget End
2014-05-31
Support Year
5
Fiscal Year
2011
Total Cost
$281,979
Indirect Cost
Name
Emory University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
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Morreall, Jordan; Kim, Alice; Liu, Yuan et al. (2015) Evidence for Retromutagenesis as a Mechanism for Adaptive Mutation in Escherichia coli. PLoS Genet 11:e1005477
Morreall, Jordan F; Petrova, Lucy; Doetsch, Paul W (2013) Transcriptional mutagenesis and its potential roles in the etiology of cancer and bacterial antibiotic resistance. J Cell Physiol 228:2257-61
Kawahara, Tsukasa; Jackson, Heather M; Smith, Susan M E et al. (2011) Nox5 forms a functional oligomer mediated by self-association of its dehydrogenase domain. Biochemistry 50:2013-25
Brégeon, Damien; Doetsch, Paul W (2011) Transcriptional mutagenesis: causes and involvement in tumour development. Nat Rev Cancer 11:218-27
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Saxowsky, Tina T; Meadows, Kellen L; Klungland, Arne et al. (2008) 8-Oxoguanine-mediated transcriptional mutagenesis causes Ras activation in mammalian cells. Proc Natl Acad Sci U S A 105:18877-82