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 #
5P01CA098993-08
Application #
8381902
Study Section
Special Emphasis Panel (ZCA1-RPRB-0)
Project Start
Project End
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
8
Fiscal Year
2012
Total Cost
$900,503
Indirect Cost
$662,803
Name
University of Vermont & St Agric College
Department
Type
DUNS #
066811191
City
Burlington
State
VT
Country
United States
Zip Code
05405
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
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
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
Maher, R L; Marsden, C G; Averill, A M et al. (2017) Human cells contain a factor that facilitates the DNA glycosylase-mediated excision of oxidized bases from occluded sites in nucleosomes. DNA Repair (Amst) 57:91-97
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
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
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
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
Cannan, Wendy J; Pederson, David S (2016) Mechanisms and Consequences of Double-Strand DNA Break Formation in Chromatin. J Cell Physiol 231:3-14
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

Showing the most recent 10 out of 61 publications