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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA093729-16
Application #
9207118
Study Section
Cancer Etiology Study Section (CE)
Program Officer
Okano, Paul
Project Start
2002-01-28
Project End
2017-12-31
Budget Start
2017-01-01
Budget End
2017-12-31
Support Year
16
Fiscal Year
2017
Total Cost
Indirect Cost
Name
University of Texas Austin
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
170230239
City
Austin
State
TX
Country
United States
Zip Code
78759
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