The broad, long-term objective of the proposed research Is to provide Insight Into how the BER and RAD51 variants In the normal population and In tumors contribute to altered DNA repair capacity, Altered DNA repair capacity can drive carcinogenesis and Is Important for designing personalized cancer therapy.
The specific aims are: (1) to test the hypothesis that variants of NTHI, NEIL1, 2, 3, and RAD51 that are found in the normal population and In tumors are linked to cancer;(2) to test the hypothesis that DNA glycosylase and RAD51 variants arising in the normal population and In tumors lead to genomic instability;and (3) to test the hypothesis that DNA repair variants Influence cellular responses to DNA damaging agents. To accomplish these alms we will express the variants in tissue culture cells and determine if they Induce cellular transformation. We will also Initiate studies to Identify additional tumor-associated variants within our collection of DNA samples Isolated from colon and breast carcinomas. We will measure the in vivo mutation frequency and generate mutation spectra to determine the types of mutations that result from cells expressing variant DNA glycosylases and Rad51. In cells expressing these variants we will also characterize responses to ionizing radiation, cisplatin, and other appropriate agents to determine if they Influence DNA repair. Information gleaned from Project 1 will guide additional biochemical and structural studies on the variants In Projects 2 and 3 as well as their Interactions with nucleosomes In Project 4. Core A will provide the bioinformatics and statistical Infrastructure for Project 1 and Core B will provide protein constructs and enzymes.
These studies will advance our understanding of how DNA repair variants contribute to individual cancer risk and how they drive carcinogenesis. Moreover, the enzyme variants present in tumors may be exploited to treat cancer.
|Lee, Andrea J; Wallace, Susan S (2016) Visualizing the Search for Radiation-damaged DNA Bases in Real Time. Radiat Phys Chem Oxf Engl 1993 128:126-133|
|Prakash, Aishwarya; Cao, Vy Bao; DoubliÃ©, Sylvie (2016) Phosphorylation Sites Identified in the NEIL1 DNA Glycosylase Are Potential Targets for the JNK1 Kinase. PLoS One 11:e0157860|
|Cannan, Wendy J; Pederson, David S (2016) Mechanisms and Consequences of Double-Strand DNA Break Formation in Chromatin. J Cell Physiol 231:3-14|
|Marsden, Carolyn G; Jensen, Ryan B; Zagelbaum, Jennifer et al. (2016) The Tumor-Associated Variant RAD51 G151D Induces a Hyper-Recombination Phenotype. PLoS Genet 12:e1006208|
|Silva, Michelle C; Morrical, Milagros D; Bryan, Katie E et al. (2016) RAD51 variant proteins from human lung and kidney tumors exhibit DNA strand exchange defects. DNA Repair (Amst) 42:44-55|
|Zhou, Jia; Fleming, Aaron M; Averill, April M et al. (2015) The NEIL glycosylases remove oxidized guanine lesions from telomeric and promoter quadruplex DNA structures. Nucleic Acids Res 43:4039-54|
|Chen, Jianhong; Morrical, Milagros D; Donigan, Katherine A et al. (2015) Tumor-associated mutations in a conserved structural motif alter physical and biochemical properties of human RAD51 recombinase. Nucleic Acids Res 43:1098-111|
|Morrical, Scott W (2015) DNA-pairing and annealing processes in homologous recombination and homology-directed repair. Cold Spring Harb Perspect Biol 7:a016444|
|Prakash, Aishwarya; DoubliÃ©, Sylvie (2015) Base Excision Repair in the Mitochondria. J Cell Biochem 116:1490-9|
|Prakash, Aishwarya; Carroll, Brittany L; Sweasy, Joann B et al. (2014) Genome and cancer single nucleotide polymorphisms of the human NEIL1 DNA glycosylase: activity, structure, and the effect of editing. DNA Repair (Amst) 14:17-26|
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