Abstract

The long term objectives of this research is to understand the cellular mechanisms by which DNA damage from agents such as ultraviolet irradiation and many carcinogens is processed to give rise to mutations. A considerable amount of the research proposed for the upcoming grant period will focus on defining the genetics and biochemistry of the products of the UmuD and UmuC genes of Escherichia coli. The UmuD and UmuC proteins, as well as their plasmid-coded analogs, MucA and MucB, play a crucial but as yet undetermined role in most chemical and radiation mutagenesis. The UmuD and UmuC proteins will be over-produced, purified, and physically characterized. The biochemical roles of UmuD and UmuC in UV and chemical mutagenesis will be studied and a umuD+ umuC+ dependent in vitro mutagenesis system will be established. The ongoing genetic analysis of the umuDC and mucAB loci will be continued. Other genetic studies of mutagenesis will be initiated in order to investigate such issues as the second role of the RecA protein in mutagenesis. Other organisms will be investigated for the presence of UmuD/UmuC functions. These studies are highly relevant to our understanding of the molecular mechanisms by which chemical carcinogens cause cancer.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA021615-09
Application #
3165584
Study Section
Genetics Study Section (GEN)
Project Start
1977-04-01
Project End
1990-03-31
Budget Start
1985-04-01
Budget End
1986-03-31
Support Year
9
Fiscal Year
1985
Total Cost
Indirect Cost

  Institution

Name
Massachusetts Institute of Technology
Department
Type
Schools of Arts and Sciences
DUNS #
City
Cambridge
State
MA
Country
United States
Zip Code

  Publications

Gruber, Charley C; Walker, Graham C (2018) Incomplete base excision repair contributes to cell death from antibiotics and other stresses. DNA Repair (Amst) :
Takahashi, Noriko; Gruber, Charley C; Yang, Jason H et al. (2017) Lethality of MalE-LacZ hybrid protein shares mechanistic attributes with oxidative component of antibiotic lethality. Proc Natl Acad Sci U S A :
Dwyer, Daniel J; Collins, James J; Walker, Graham C (2015) Unraveling the physiological complexities of antibiotic lethality. Annu Rev Pharmacol Toxicol 55:313-32
Belenky, Peter; Ye, Jonathan D; Porter, Caroline B M et al. (2015) Bactericidal Antibiotics Induce Toxic Metabolic Perturbations that Lead to Cellular Damage. Cell Rep 13:968-80
Shrivastav, Nidhi; Fedeles, Bogdan I; Li, Deyu et al. (2014) A chemical genetics analysis of the roles of bypass polymerase DinB and DNA repair protein AlkB in processing N2-alkylguanine lesions in vivo. PLoS One 9:e94716
Opperman, Timothy J; Kwasny, Steven M; Kim, Hong-Suk et al. (2014) Characterization of a novel pyranopyridine inhibitor of the AcrAB efflux pump of Escherichia coli. Antimicrob Agents Chemother 58:722-33
Kath, James E; Jergic, Slobodan; Heltzel, Justin M H et al. (2014) Polymerase exchange on single DNA molecules reveals processivity clamp control of translesion synthesis. Proc Natl Acad Sci U S A 111:7647-52
Pandey, Shree P; Winkler, Jonathan A; Li, Hu et al. (2014) Central role for RNase YbeY in Hfq-dependent and Hfq-independent small-RNA regulation in bacteria. BMC Genomics 15:121
Penterman, Jon; Singh, Pradeep K; Walker, Graham C (2014) Biological cost of pyocin production during the SOS response in Pseudomonas aeruginosa. J Bacteriol 196:3351-9
Dwyer, Daniel J; Belenky, Peter A; Yang, Jason H et al. (2014) Antibiotics induce redox-related physiological alterations as part of their lethality. Proc Natl Acad Sci U S A 111:E2100-9

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