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).

Public Health Relevance

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

National Institute of Health (NIH)
Research Program Projects (P01)
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Special Emphasis Panel (ZCA1)
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University of Vermont & St Agric College
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Cannan, Wendy J; Tsang, Betty P; Wallace, Susan S et al. (2014) Nucleosomes suppress the formation of double-strand DNA breaks during attempted base excision repair of clustered oxidative damages. J Biol Chem 289:19881-93
Wallace, Susan S (2014) Base excision repair: a critical player in many games. DNA Repair (Amst) 19:14-26
Nelson, Shane R; Dunn, Andrew R; Kathe, Scott D et al. (2014) Two glycosylase families diffusively scan DNA using a wedge residue to probe for and identify oxidatively damaged bases. Proc Natl Acad Sci U S A 111:E2091-9
Lubula, Mulu Y; Poplawaski, Amanda; Glass, Karen C (2014) Crystallization and preliminary X-ray diffraction analysis of the BRPF1 bromodomain in complex with its H2AK5ac and H4K12ac histone-peptide ligands. Acta Crystallogr F Struct Biol Commun 70:1389-93
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
Sjolund, Ashley; Nemec, Antonia A; Paquet, Nicolas et al. (2014) A germline polymorphism of thymine DNA glycosylase induces genomic instability and cellular transformation. PLoS Genet 10:e1004753
Lee, Andrea J; Warshaw, David M; Wallace, Susan S (2014) Insights into the glycosylase search for damage from single-molecule fluorescence microscopy. DNA Repair (Amst) 20:23-31
Prakash, Aishwarya; Eckenroth, Brian E; Averill, April M et al. (2013) Structural investigation of a viral ortholog of human NEIL2/3 DNA glycosylases. DNA Repair (Amst) 12:1062-71
Liu, Minmin; Doublie, Sylvie; Wallace, Susan S (2013) Neil3, the final frontier for the DNA glycosylases that recognize oxidative damage. Mutat Res 743-744:4-11
Odell, Ian D; Wallace, Susan S; Pederson, David S (2013) Rules of engagement for base excision repair in chromatin. J Cell Physiol 228:258-66

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