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.
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.
|Malhotra, Akshay; Sharma, Uttam; Puhan, Shyamly et al. (2018) Stabilization of miRNAs in esophageal cancer contributes to radioresistance and limits efficacy of therapy. Biochimie 156:148-157|
|Zhao, Junhua; Wang, Guliang; Del Mundo, Imee M et al. (2018) Distinct Mechanisms of Nuclease-Directed DNA-Structure-Induced Genetic Instability in Cancer Genomes. Cell Rep 22:1200-1210|
|Nadella, Vinod; Singh, Sandhya; Jain, Aklank et al. (2018) Low dose radiation primed iNOS?+?M1macrophages modulate angiogenic programming of tumor derived endothelium. Mol Carcinog 57:1664-1671|
|Kononenko, Artem V; Ebersole, Thomas; Vasquez, Karen M et al. (2018) Mechanisms of genetic instability caused by (CGG)n repeats in an experimental mammalian system. Nat Struct Mol Biol 25:669-676|
|Malhotra, Akshay; Jain, Manju; Prakash, Hridayesh et al. (2017) The regulatory roles of long non-coding RNAs in the development of chemoresistance in breast cancer. Oncotarget 8:110671-110684|
|Wang, Guliang; Vasquez, Karen M (2017) Effects of Replication and Transcription on DNA Structure-Related Genetic Instability. Genes (Basel) 8:|
|Khandelwal, Akanksha; Malhotra, Akshay; Jain, Manju et al. (2017) The emerging role of long non-coding RNA in gallbladder cancer pathogenesis. Biochimie 132:152-160|
|Del Mundo, Imee Marie A; Zewail-Foote, Maha; Kerwin, Sean M et al. (2017) Alternative DNA structure formation in the mutagenic human c-MYC promoter. Nucleic Acids Res 45:4929-4943|
|Reh, Wade A; Nairn, Rodney S; Lowery, Megan P et al. (2017) The homologous recombination protein RAD51D protects the genome from large deletions. Nucleic Acids Res 45:1835-1847|
|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|
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