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
|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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