Abstract

This project is focused on genetic and biochemical studies designed to test the role of FEN-1 in trinucleotide repeat expansion. One set of goals is to examine the role of FEN-1 in trinucleotide repeat expansion using mouse models. Alterations in a variety of micro satellite loci including large trinucleotide transgenes will be studied using single molecule analysis of DNA from somatic and germline tissues. Another collection of goals is to test a specific model for how inhibition of FEN-1 activity can lead to expansion mutations as a consequence of alterations in its role in the processing of Okazaki fragments. The biochemical properties of FEN1 and additional Okazaki fragment processing enzymes including PCNA, RNAse H1 and ligase I will be studied to assess their potential roles in genetic instability.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
5P01AG017179-03
Application #
6588089
Study Section
Special Emphasis Panel (ZAG1)
Project Start
2002-05-01
Project End
2003-03-31
Budget Start
Budget End
Support Year
3
Fiscal Year
2002
Total Cost
$241,233
Indirect Cost

  Institution

Name
University of Southern California
Department
Type
DUNS #
041544081
City
Los Angeles
State
CA
Country
United States
Zip Code
90089

  Publications

Chambers, Eric J; Price, Eric A; Bayramyan, Melina C et al. (2003) Computation of DNA backbone conformations. J Biomol Struct Dyn 21:111-25
Karanjawala, Zarir E; Hsieh, Chih-Lin; Lieber, Michael R (2003) Overexpression of Cu/Zn superoxide dismutase is lethal for mice lacking double-strand break repair. DNA Repair (Amst) 2:285-94
Hartenstine, Michael J; Goodman, Myron F; Petruska, John (2002) Weak strand displacement activity enables human DNA polymerase beta to expand CAG/CTG triplet repeats at strand breaks. J Biol Chem 277:41379-89
Karanjawala, Zarir E; Adachi, Noritaka; Irvine, Ryan A et al. (2002) The embryonic lethality in DNA ligase IV-deficient mice is rescued by deletion of Ku: implications for unifying the heterogeneous phenotypes of NHEJ mutants. DNA Repair (Amst) 1:1017-26
Goodman, Myron F (2002) Error-prone repair DNA polymerases in prokaryotes and eukaryotes. Annu Rev Biochem 71:17-50
Romero, R M; Rojsitthisak, P; Haworth, I S (2001) DNA interstrand crosslink formation by mechlorethamine at a cytosine-cytosine mismatch pair: kinetics and sequence dependence. Arch Biochem Biophys 386:143-53
Poltoratsky, V; Woo, C J; Tippin, B et al. (2001) Expression of error-prone polymerases in BL2 cells activated for Ig somatic hypermutation. Proc Natl Acad Sci U S A 98:7976-81
Rojsitthisak, P; Romero, R M; Haworth, I S (2001) Extrahelical cytosine bases in DNA duplexes containing d[GCC](n).d[GCC](n) repeats: detection by a mechlorethamine crosslinking reaction. Nucleic Acids Res 29:4716-23
Karanjawala, Z E; Shi, X; Hsieh, C L et al. (2000) The mammalian FEN-1 locus: structure and conserved sequence features. Microb Comp Genomics 5:173-7
Hartenstine, M J; Goodman, M F; Petruska, J (2000) Base stacking and even/odd behavior of hairpin loops in DNA triplet repeat slippage and expansion with DNA polymerase. J Biol Chem 275:18382-90