Aging and cancer are inextricably linked. Genome instability is common to both aging and cancer, whereby genetic instability and cancer risk increase with age. However, there is a fundamental gap in understanding the mechanisms that predispose us to increased genetic instability as we age. Thus, the overall objective of this application is to fill this gap in knowledge. Mutations are not random, and there are endogenous mutation ?hotspot? regions of the genome. Importantly, many of these cancer-assoicated mutation hotspots co-localize with, and are enriched at sequences capable of adopting alternatively structured DNA (i.e. non-B DNA), implicating these sequences in cancer etiology. We have discovered that naturally occurring non-B DNA; e.g., Z-DNA and H-DNA, is mutagenic in mammals, and this DNA structure-induced mutation increases with age. However, the mechanisms involved in the age-related propagation of genetic instability at these hotspots are unclear. Thus, a goal is to determine the mechanisms involved in DNA structure-induced genetic instability, and the impact of increased age on the generation of these endogenous mutation hotspots. We have also found that non-B DNA is processed by DNA repair and replication proteins. These findings provide the basis for the scientific premise going forward to test the novel hypothesis that cancer relevant DNA structure-induced genetic instability increases with age, because with age, non-B DNA (i.e. an endogenous mutation hotspot) becomes increasingly refractory to repair; moreover, non-B DNA is subject to error-prone processing that increases with age. Both mechanisms lead to the generation of age-dependent mutations. The long-term goals are to elucidate the impact of aging on genetic instability at mutation hotspots, to determine the mechanisms of age-related, and tissue-specific DNA structure-induced genetic instability in cancer etiology, and to develop novel approaches to reduce genetic instability to prevent and/or treat age-related disease. The objectives are to determine the role(s) of age in DNA structure-induced genomic instability in specific tissues of mice, and to identify the mechanisms of replication-dependent and -independent genetic instability. We will use novel mutation-reporter mice that we have developed to determine the effects of age on the mutagenic potential of non-B DNA sequences, and determine the mechanisms of the processing of these mutagenic sequences. This is innovative because it will test the novel hypothesis that DNA structure-induced genetic instability increases with age in mammals, and that these structure-forming sequences are processed by DNA repair mechanisms whose efficiency decline with age. The expected contribution is the elucidation of the impact of age on genetic instability and of the mechanisms involved in the generation of endogeous mutation hotspots in cancer, to provide a better understanding of age-related disease etiology. This is significant because the results will aid in the development of new strategies to mitigate age-related diseases.

Public Health Relevance

The proposed research is relevant to public health because increased age is a known contributing factor to increased genomic instability and cancer risk; however, the mechanisms involved are not clearly defined, particularly why certain regions of the genome are ?hotspots? for mutations. We will explore the mechanisms of age-related genetic instability at these hotspots. Results from the proposed study will assist in the elucidation of the mechanisms involved in genomic instability at endogenous hotspots, and the the impact of aging on these mechanisms, which will aid in achieving our long-term goal of reducing age-related disease incidence.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA093729-19
Application #
9838724
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Okano, Paul
Project Start
2002-01-28
Project End
2022-12-31
Budget Start
2020-01-01
Budget End
2020-12-31
Support Year
19
Fiscal Year
2020
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
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

Showing the most recent 10 out of 60 publications