Translocations are known to be involved in the etiology of many cancers, and DNA double-strand breaks (DSBs) are an essential first step in the formation of many oncogenic translocations. However, there is a fundamental gap in understanding the mechanisms involved in the generation of DSBs at breakage """"""""hotspots"""""""" in oncogenes. For example, chromosomal breakages frequently occur at genomic """"""""hotspots"""""""" and can result in translocation-related disease. Interestingly, chromosomal breakpoint """"""""hotspots"""""""" are often mapped near repetitive DNA sequences capable of adopting alternatively structured DNA (i.e., non-B DNA, such as H-DNA and Z-DNA), implicating these structures in cancer etiology. The discoveries from the applicant's laboratory that naturally occurring Z-DNA (found at a breakpoint """"""""hotpspot"""""""" in BCL-2) and H-DNA (found near a translocation breakpoint """"""""hotspot"""""""" in c-MYC) are highly mutagenic and can induce DSBs in mammalian cells and in mice, provide the basis for the rationale going forward to test the novel hypotheses that: 1) non-B DNA structures are recognized as """"""""damage"""""""" and are processed by DNA repair proteins;2) non-B DNA presents a block to DNA and RNA polymerases resulting in DSBs;and 3) non-B DNA-induced genetic instability increases with age in mammals, relevant to translocation-related cancer etiology. The long-term goals of this renewal application are to determine the mechanisms of DNA structure-induced genetic instability in cancer etiology, elucidate the mechanisms involved in cancer-associated translocations, and develop novel approaches to reduce genetic instability to prevent and/or treat cancer. The immediate objectives of this application are to elucidate the mechanisms of chromosomal breakage in the cancer-related c-MYC and BCL-2 genes, and to determine the roles of DNA repair, replication, and transcription in DNA structure-induced genomic instability. To accomplish our goal, we will use human cells and novel mutation-reporter mice in the following aims: 1) determine the roles of DNA repair pathways in the mutagenic potential of non-B DNA found in the cancer- related c-MYC and BCL-2 genes;2) elucidate the mechanisms of replication-independent and replication- dependent processing of non-B DNA structures in human cells;3) assess the effects of transcription on non-B DNA-induced genetic instability in human cells;and 4) evaluate the effects of aging on the mutagenic potential of non-B DNA-forming sequences from the human c-MYC and BCL-2 genes in tissues of transgenic mice. The proposed work is innovative because it will test the novel hypothesis that DNA structure, in the absence of DNA damage per se, is recognized and processed by the repair machinery, and that these structures are involved in cancer etiology. The expected contribution of the proposed research is to elucidate the mechanisms of chromosomal breakage in oncogenes to better understand cancer etiology, which is significant because the results will aid in the development of new strategies to help reduce cancer incidence.

Public Health Relevance

The proposed research is relevant to public health because the elucidation of the mechanisms of DNA structure-induced genetic instability is ultimately expected to increase understanding of the etiology of disorders resulting from genomic instability (such as cancer), as well as the development of novel approaches to prevent or treat such diseases. Thus, the proposed research is relevant to the part of NIH's mission that pertains to developing fundamental new knowledge that will help to reduce the burden of human cancer and other diseases associated with genomic instability.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Cancer Etiology Study Section (CE)
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Okano, Paul
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University of Texas Austin
Schools of Pharmacy
United States
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Wang, Guliang; Zhao, Junhua; Vasquez, Karen M (2016) Detection of cis- and trans-acting Factors in DNA Structure-Induced Genetic Instability Using In silico and Cellular Approaches. Front Genet 7:135
Mukherjee, Anirban; Vasquez, Karen M (2016) HMGB1 interacts with XPA to facilitate the processing of DNA interstrand crosslinks in human cells. Nucleic Acids Res 44:1151-60
Bacolla, Albino; Tainer, John A; Vasquez, Karen M et al. (2016) Translocation and deletion breakpoints in cancer genomes are associated with potential non-B DNA-forming sequences. Nucleic Acids Res 44:5673-88
Lu, Steve; Wang, Guliang; Bacolla, Albino et al. (2015) Short Inverted Repeats Are Hotspots for Genetic Instability: Relevance to Cancer Genomes. Cell Rep :
Bacolla, Albino; Wang, Guliang; Vasquez, Karen M (2015) New Perspectives on DNA and RNA Triplexes As Effectors of Biological Activity. PLoS Genet 11:e1005696
Bacolla, Albino; Zhu, Xiao; Chen, Hanning et al. (2015) Local DNA dynamics shape mutational patterns of mononucleotide repeats in human genomes. Nucleic Acids Res 43:5065-80
Temiz, Nuri A; Donohue, Duncan E; Bacolla, Albino et al. (2015) The somatic autosomal mutation matrix in cancer genomes. Hum Genet 134:851-64
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
Bacolla, Albino; Cooper, David N; Vasquez, Karen M (2014) Mechanisms of base substitution mutagenesis in cancer genomes. Genes (Basel) 5:108-46
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

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