DNA damage and repair are fundamental to human health and disease. The long-term objectives of this application are to: expand our understanding of the role of DNA helical distortions in DNA damage recognition and processing;determine the factors influencing DNA structure-induced genetic instability; elucidate potential mechanisms involved in translocations associated with certain cancers;and further the development of novel approaches to reduce genetic instability in human cells. In the short term, we will pursue our recent discovery that helical distortions induced by naturally occurring Z-DNA and H-DNA structures are highly mutagenic and can induce DNA double-strand breaks (DSBs) in mammalian cells. We propose to study the effect of DNA helical distortions on genomic instability in plasmid-based systems as well as on chromosomes in human cells and in transgenic mutation-reporter mice. We will focus on the H- DNA-forming sequence located near the translocation breakpoint in the human c-MYC promoter and the Z- DNA sequence located at a chromosomal breakpoint in the human BCL-2 gene, found in lymphomas and leukemias. We will determine the role(s) of DNA repair, replication and transcription in the structure-induced genetic instability. We will use our expertise in the introduction of site-specific DNA helical distortions in the form of well-defined intermolecular triplex structures to test our hypothesis that certain types of DNA helical distortions (in the presence or absence of DNA damage per se) are recognized by the DNA repair machinery in human cells. The new information obtained from these studies will provide insight into the mechanisms of non-B DNA-induced genetic instability;the rate-limiting step in human DNA repair (i.e.distortion/damage recognition);and the overlap between nucleotide excision repair and mismatch repair in processing DNA helical distortions. It will also identify the proteins involved in the generation of DSBs induced bynon- canonical DNA structures formed at sequences that map to translocation breakpoints in human cancers. These discoveries should lead to a better understanding of the pathogenesis of cancers and other diseases that are caused by DNA damage and naturally occurring helical distortions, and ultimately to the development of new approaches to treatment and prevention.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA093729-11
Application #
8119778
Study Section
Cancer Etiology Study Section (CE)
Program Officer
Okano, Paul
Project Start
2002-01-28
Project End
2012-12-31
Budget Start
2012-01-01
Budget End
2012-12-31
Support Year
11
Fiscal Year
2012
Total Cost
$306,828
Indirect Cost
$107,706
Name
University of Texas Austin
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
170230239
City
Austin
State
TX
Country
United States
Zip Code
78712
Bacolla, Albino; Cooper, David N; Vasquez, Karen M (2014) Mechanisms of base substitution mutagenesis in cancer genomes. Genes (Basel) 5:108-46
Wang, Guliang; Vasquez, Karen M (2014) Impact of alternative DNA structures on DNA damage, DNA repair, and genetic instability. DNA Repair (Amst) 19:143-51
Boulware, Stephen B; Christensen, Laura A; Thames, Howard et al. (2014) Triplex-forming oligonucleotides targeting c-MYC potentiate the anti-tumor activity of gemcitabine in a mouse model of human cancer. Mol Carcinog 53:744-52
Wang, Guliang; Gaddis, Sally; Vasquez, Karen M (2013) Methods to detect replication-dependent and replication-independent DNA structure-induced genetic instability. Methods 64:67-72
Vasquez, Karen M; Wang, Guliang (2013) The yin and yang of repair mechanisms in DNA structure-induced genetic instability. Mutat Res 743-744:118-31
Bacolla, Albino; Cooper, David N; Vasquez, Karen M (2013) DNA structure matters. Genome Med 5:51
Bacolla, Albino; Temiz, Nuri A; Yi, Ming et al. (2013) Guanine holes are prominent targets for mutation in cancer and inherited disease. PLoS Genet 9:e1003816
Jain, Aklank; Bacolla, Albino; Del Mundo, Imee M et al. (2013) DHX9 helicase is involved in preventing genomic instability induced by alternatively structured DNA in human cells. Nucleic Acids Res 41:10345-57
Bacolla, Albino; Wang, Guliang; Jain, Aklank et al. (2011) Non-B DNA-forming sequences and WRN deficiency independently increase the frequency of base substitution in human cells. J Biol Chem 286:10017-26
Mukherjee, Anirban; Vasquez, Karen M (2011) Triplex technology in studies of DNA damage, DNA repair, and mutagenesis. Biochimie 93:1197-208

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