Genomic stability is vital to the health of the organism and the preservation of the species. This stability is threatened by DNA damage from endogenous and exogenous sources;such damage can cause mutations that lead to cancer and genetic disorders. To cope with DNA damage all organisms have both damage specific and general DNA repair pathways. This arsenal includes the newly-discovered Y-family DNA polymerases that can replicate damaged DNA. However, these polymerases are highly error-prone, making frequent errors even when replicating undamaged DNA. If the mutagenic activities of these polymerases are not controlled, they could become a potent source of genetic instability. The goal of this research project is to elucidate the cellular pathways that regulate error-prone DNA polymerases. The approach taken here focuses on DNA polymerase IV from the bacterium Escherichia coli as a model. E. coli's DNA polymerase IV is very closely related to the error-prone polymerases that are active in higher organisms, including humans. The mechanisms by which this simple bacterium controls the activity of Pol IV may provide a paradigm for similar mechanisms in all organisms. A number of cellular factors that affect Pol IV have already been identified. The research proposed will establish how these control the abundance and the activity of Pol IV.
The specific aims are: (1) to determine how the abundance of Pol IV is regulated;(2) to establish how the mutagenic activity of Pol IV is regulated;(3) to identify and characterize protein interactions that affect Pol IV.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM065175-08
Application #
8126390
Study Section
Special Emphasis Panel (ZRG1-IDM-A (02))
Program Officer
Janes, Daniel E
Project Start
2002-04-01
Project End
2014-08-31
Budget Start
2011-09-01
Budget End
2014-08-31
Support Year
8
Fiscal Year
2011
Total Cost
$250,861
Indirect Cost
Name
Indiana University Bloomington
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
006046700
City
Bloomington
State
IN
Country
United States
Zip Code
47401
Mallik, Sarita; Popodi, Ellen M; Hanson, Andrew J et al. (2015) Interactions and Localization of Escherichia coli Error-Prone DNA Polymerase IV after DNA Damage. J Bacteriol 197:2792-809
Williams, Ashley B; Foster, Patricia L (2012) Stress-Induced Mutagenesis. EcoSal Plus 5:
Sakofsky, Cynthia J; Foster, Patricia L; Grogan, Dennis W (2012) Roles of the Y-family DNA polymerase Dbh in accurate replication of the Sulfolobus genome at high temperature. DNA Repair (Amst) 11:391-400
Sladewski, Thomas E; Hetrick, Kyle M; Foster, Patricia L (2011) Escherichia coli Rep DNA helicase and error-prone DNA polymerase IV interact physically and functionally. Mol Microbiol 80:524-41
Foster, Patricia L (2011) Comment on ""A bacterium that can grow by using arsenic instead of phosphorus"". Science 332:1149; author reply 1149
Williams, Ashley B; Hetrick, Kyle M; Foster, Patricia L (2011) Double-Strand Break Repair and Holliday Junction Processing Are Required for Chromosome Processing in Stationary-Phase Escherichia coli Cells. G3 (Bethesda) 1:417-26
Storvik, Kimberly A M; Foster, Patricia L (2011) The SMC-like protein complex SbcCD enhances DNA polymerase IV-dependent spontaneous mutation in Escherichia coli. J Bacteriol 193:660-9
Williams, Ashley B; Hetrick, Kyle M; Foster, Patricia L (2010) Interplay of DNA repair, homologous recombination, and DNA polymerases in resistance to the DNA damaging agent 4-nitroquinoline-1-oxide in Escherichia coli. DNA Repair (Amst) 9:1090-7
Storvik, Kimberly A M; Foster, Patricia L (2010) RpoS, the stress response sigma factor, plays a dual role in the regulation of Escherichia coli's error-prone DNA polymerase IV. J Bacteriol 192:3639-44
Foster, Patricia L (2007) Stress-induced mutagenesis in bacteria. Crit Rev Biochem Mol Biol 42:373-97

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