Abstract

This is an application to continue a 23-year study of eukaryotic DNA polymerases, which originally focused on human polymerase alpha, but now also involves polymerase delta, and their functions in chromosomal DNA replication in vivo. Previous work with DNA polymerase alpha has involved in-depth analysis of the functions of active site residues in every aspect of polymerase function. A central feature of new work will be to test the hypothesis that mutations in genes that play a critical role in DNA replication can be an early event on tumorigenesis and a source of genetic instability observed in cancer cells. The investigators will initially test the mutational effect of altered forms of pol alpha and delta using fission yeast as the model. The progression of alterations in growth properties over generations will be examined. The work will then be developed in human cells and ultimately in an animal model. In another area, they have shown that pol alpha can interact with SV 40T antigen, BPV E1, and HSV UL9 as part of the process of initiation of viral replication. Experiments are proposed to analyze the interaction of pol alpha with the E1 and E2 replication proteins of HPV-11.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA014835-26
Application #
2871647
Study Section
Biochemistry Study Section (BIO)
Program Officer
Mietz, Judy
Project Start
1978-07-01
Project End
2002-01-31
Budget Start
1999-02-01
Budget End
2000-01-31
Support Year
26
Fiscal Year
1999
Total Cost
Indirect Cost

  Institution

Name
Stanford University
Department
Pathology
Type
Schools of Medicine
DUNS #
800771545
City
Stanford
State
CA
Country
United States
Zip Code
94305

  Publications

Zhou, Yanjiao; Wang, Teresa S-F (2004) A coordinated temporal interplay of nucleosome reorganization factor, sister chromatin cohesion factor, and DNA polymerase alpha facilitates DNA replication. Mol Cell Biol 24:9568-79
Uchiyama, Masashi; Wang, Teresa S-F (2004) The B-subunit of DNA polymerase alpha-primase associates with the origin recognition complex for initiation of DNA replication. Mol Cell Biol 24:7419-34
Kai, Mihoko; Wang, Teresa S-F (2003) Checkpoint responses to replication stalling: inducing tolerance and preventing mutagenesis. Mutat Res 532:59-73
Gutierrez, Pedro J A; Wang, Teresa S-F (2003) Genomic instability induced by mutations in Saccharomyces cerevisiae POL1. Genetics 165:65-81
Samudrala, R; Xia, Y; Levitt, M et al. (2000) Probing structure-function relationships of the DNA polymerase alpha-associated zinc-finger protein using computational approaches. Pac Symp Biocomput :179-90
Conger, K L; Liu, J S; Kuo, S R et al. (1999) Human papillomavirus DNA replication. Interactions between the viral E1 protein and two subunits of human dna polymerase alpha/primase. J Biol Chem 274:2696-705
Kelman, Z; Zuo, S; Arroyo, M P et al. (1999) The C-terminal region of Schizosaccaromyces pombe proliferating cell nuclear antigen is essential for DNA polymerase activity. Proc Natl Acad Sci U S A 96:9515-20
Liu, V F; Bhaumik, D; Wang, T S (1999) Mutator phenotype induced by aberrant replication. Mol Cell Biol 19:1126-35
Lee, S S; Dong, Q; Wang, T S et al. (1995) Interaction of herpes simplex virus 1 origin-binding protein with DNA polymerase alpha. Proc Natl Acad Sci U S A 92:7882-6
Dong, Q; Wang, T S (1995) Mutational studies of human DNA polymerase alpha. Lysine 950 in the third most conserved region of alpha-like DNA polymerases is involved in binding the deoxynucleoside triphosphate. J Biol Chem 270:21563-70

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