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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA098993-09
Application #
8543548
Study Section
Special Emphasis Panel (ZCA1-RPRB-0)
Project Start
Project End
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
9
Fiscal Year
2013
Total Cost
$318,542
Indirect Cost
$89,516
Name
University of Vermont & St Agric College
Department
Type
DUNS #
066811191
City
Burlington
State
VT
Country
United States
Zip Code
05405
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Marsden, Carolyn G; Dragon, Julie A; Wallace, Susan S et al. (2017) Base Excision Repair Variants in Cancer. Methods Enzymol 591:119-157
Galick, Heather A; Marsden, Carolyn G; Kathe, Scott et al. (2017) The NEIL1 G83D germline DNA glycosylase variant induces genomic instability and cellular transformation. Oncotarget 8:85883-85895
Robey-Bond, Susan M; Benson, Meredith A; Barrantes-Reynolds, Ramiro et al. (2017) Probing the activity of NTHL1 orthologs by targeting conserved amino acid residues. DNA Repair (Amst) 53:43-51
Cannan, Wendy J; Rashid, Ishtiaque; Tomkinson, Alan E et al. (2017) The Human Ligase III?-XRCC1 Protein Complex Performs DNA Nick Repair after Transient Unwrapping of Nucleosomal DNA. J Biol Chem 292:5227-5238
Silva, Michelle C; Bryan, Katie E; Morrical, Milagros D et al. (2017) Defects in recombination activity caused by somatic and germline mutations in the multimerization/BRCA2 binding region of human RAD51 protein. DNA Repair (Amst) 60:64-76
Zhou, Jia; Chan, Jany; Lambelé, Marie et al. (2017) NEIL3 Repairs Telomere Damage during S Phase to Secure Chromosome Segregation at Mitosis. Cell Rep 20:2044-2056
Prakash, Aishwarya; Moharana, Kedar; Wallace, Susan S et al. (2017) Destabilization of the PCNA trimer mediated by its interaction with the NEIL1 DNA glycosylase. Nucleic Acids Res 45:2897-2909
Lee, Andrea J; Wallace, Susan S (2017) Hide and seek: How do DNA glycosylases locate oxidatively damaged DNA bases amidst a sea of undamaged bases? Free Radic Biol Med 107:170-178
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

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