The specific aims of Core A are to provide informatics and statistics services, of which there are four:
Specific Aim 1 Human gene variant database: To maintain a database of human germline or somatic sequence variation in five enzymes involved in DNA repair and recombination: NTHL1, NEIL1-3 and RAD51 Specific Aim 2 Prediction of the functional consequences of genetic variation: To use computational methods to identify germline or somatic sequence variants having, with high probability, altered function.
Specific Aim 3 Enzyme kinetics: To identify sequence variants that have altered catalytic function by designing and analyzing enzyme kinetics experiments.
Specific Aim 4 l /lutation spectrum analysis: To identify sequence variants that show alter genomic stability in cellular studies by analyzing mutation spectra. Core A services are aligned with the test of our central hypothesis, that defects in the enzyme families we study result in aberrant base excision and homology-directed repair which is the engine driving human carcinogenesis. The gene variant database and predictions of the functional consequences of genetic variation (Aims 1-2) will be used by Projects 1-3 to identify enzyme sequence variants for biochemical and cellular studies. The projects will produce data from biochemical and cellular studies, which will then be used by Core A to evaluate the consequences of genetic variation for catalysis (Aim 3, Enzyme kinetics analysis) and genomic stability (Aim 4, Mutation spectrum analysis).
Core A will play an integral role in studies proposed by each Project and Core, both in experiment design and data analysis. Informatics and statistical services will support Project 1 Aims 1-3, Project 2 Aims 2-3, Project 3 Aims 2-3, Project 4 Aims 1-2, and Core B Aims 1-2. We expect the results of the studies proposed to advance our understanding of how variants in repair enzymes contribute to cancer susceptibility and as well provide useful targets for cancer therapy
|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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