Base excision repair (BER) is a major pathway that functions to maintain genome stability. During the past few years many human germline and tumor genomes have been sequenced, resulting in the identification of mutations in a number of genes including those that function in BER. However, little is known about these mutations because many of them are rare, precluding population-based genetic studies. The rationale is that functional characterization of these germline and somatic variants will provide important insights into their functions with specific regard to human cancer. The broad, long-term objectives of the proposed research are to determine if there is a link between the presence of variants in the BER genes and human cancer. The other objective is to determine if and how mutations in these genes impact cancer therapy.
The specific aims are 1) To test the hypothesis that human germline and somatic variants of the NEIL1, 2, 3, NTHL1 and OGG1 DNA glycosylases exhibit functional phenotypes related to the etiology of human cancer; 2) To test the hypothesis that germline and somatic variants of the human DNA glycosylases NEIL1, 2, 3, NTHL1, and OGG1 have the potential to impact cancer treatment. Core A, in collaboration with the other projects, will identify variants for functional characterization. Project 1 will characterize variants that exhibit functional and/or structural defects identified in Projects 2, 3, and 4. A combined genetics and cell biology approach will be used to characterize these variants and assess their ability to induce genomic instability, cellular transformation, and to impact responses to chemotherapies. Project 1 will also participate in the characterization of the biological phenotypes of mutants produced in Project 4.

Public Health Relevance

The relevance of these studies is that they have the potential to elucidate molecular mechanisms associated with the development of cancer and with its therapy. The results are likely to be informative in clinical decision- making processes.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
2P01CA098993-11A1
Application #
9209395
Study Section
Special Emphasis Panel (ZCA1-RPRB-F (O1))
Project Start
2004-09-03
Project End
2022-04-30
Budget Start
2016-09-01
Budget End
2017-08-31
Support Year
11
Fiscal Year
2017
Total Cost
$370,895
Indirect Cost
$127,620
Name
University of Vermont & St Agric College
Department
Type
Domestic Higher Education
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

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