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Award Abstract #0964728

Regulation of Type II Restriction-Modification Systems

Division of Molecular and Cellular Biosciences
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Initial Amendment Date: March 3, 2010
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Latest Amendment Date: February 18, 2012
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Award Number: 0964728
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Award Instrument: Continuing grant
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Program Manager: Susannah Gal
MCB Division of Molecular and Cellular Biosciences
BIO Directorate for Biological Sciences
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Start Date: March 1, 2010
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End Date: August 31, 2013 (Estimated)
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Awarded Amount to Date: $569,999.00
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Investigator(s): Robert Blumenthal robert.blumenthal@utoledo.edu (Principal Investigator)
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Sponsor: University of Toledo Health Science Campus
3000 Arlington Ave.
Toledo, OH 43614-2595 (419)383-4252
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NSF Program(s): Genetic Mechanisms,
Systems and Synthetic Biology
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Program Reference Code(s): 1116, 7465, 9183, BIOT
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Program Element Code(s): 1112, 8011


Intellectual Merit:

The biosphere is dominated by over 10e30 bacteria and archaea, a number roughly equivalent to the number of seconds since the "Big Bang". Since bacteria are asexual, their rapid acquisition of new genes (for things like antibiotic resistance or ability to degrade specific chemicals) depends on the huge amount of gene exchange between species. Despite its critical importance, what controls the rate of this gene flow between bacteria is poorly understood. But it does seem clear that restriction-modification (RM) systems play a key role. RM systems produce two enzymes, a nuclease that cuts unprotected DNA (such as what enters from another cell or a bacterial virus), and a methyltransferase that protects the bacterium's own DNA from the nuclease. Many basic questions about the functioning and roles of these systems remain. Given the great importance of RM systems for understanding ongoing bacterial evolution, with implications for everything from plant diseases through biogeochemistry and global warming, it is critical that this deficiency in our understanding be addressed.

The purpose of this project is to elucidate the regulatory design of a C protein-controlled model RM system, and how it acts in a living bacterial cell. The C protein activates transcription of its own gene, and of the downstream nuclease gene, and as a result nuclease expression is delayed until C protein accumulates. The first aim is to determine the range of acceptable relative levels of a paired nuclease and methyltransferase. If the methyltransferase/nuclease ratio is too low, cells may die from DNA damage. If this ratio is too high, the entire population may be killed by virus (phage) that escaped the nuclease and became methylated. The second aim determines naturally occurring changes in relative nuclease and methyltransferase levels, under a range of growth conditions including stresses. The third aim is to characterize the time sensitive control system that controls production of the nuclease. Mathematical modeling has provided predictions that will be tested, to see if the system design is accurately understood.

Broader Impacts:

An integral aspect of the project is to promote education and research training of scientists, ranging from high school science teachers through postdoctoral fellows. The teachers and undergraduates will each study one of the many already cloned but uncharacterized C protein orthologs. High school science teachers and undergraduate science majors will be recruited for summer research internships. The laboratory members will continue to host high school students for science fair projects and will do volunteer biology/career teaching at high schools. Additionally, at least one graduate student and one postdoctoral fellow will be encouraged to earn certificates in bioinformatics as part of their training. These individuals will be well prepared to contribute to the burgeoning field of bacterial genomics. The project will also enrich graduate level teaching and further promote the application to bacterial studies of mathematical modeling.


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Liu, Y, Zhang, X, Blumenthal, RM, and Cheng, XC. "A common mode of recognition for methylated CpG," Trends in Biochemical Sciences, v.38, 2013, p. 177. 

Liang J, and Blumenthal RM. "Naturally-occurring, dually-functional fusions between restriction endonucleases and regulatory proteins," BMC Evolutionary Biology, v.13, 2013, p. 218. 

Williams K, Savageau MA, and Blumenthal RM. "A bistable hysteretic switch in an activator-repressor regulated restriction-modification system," Nucleic Acids Research, v.41, 2013, p. 6045. 

Liu, Y, Zhang, X, Blumenthal, RM, and Cheng, X. "A common mode of recognition for methylated CpG," Trends Biochem Sci, v.38, 2013, p. 177-183. 

Kaw MK, Blumenthal RM. "Translational independence between overlapping genes for a restriction endonuclease and its transcriptional regulator," BMC Mol Biol, v.11, 2010, p. 87. 

Cheng X, Blumenthal RM. "Coordinated chromatin control: structural and functional linkage of DNA and histone methylation," Biochemistry, v.49, 2010, p. 2999. 


Robert M. Blumenthal (and 25 others). "Modifications of Nuclear DNA and its Regulatory Proteins", 03/01/2011-02/29/2012, , Xiaodong Cheng
Robert M. Blumenthal"Progress in Molecular Biology and Translational Science",  2011, "Vol 101, Academic Press, ISBN 978-0-12-387685-0, ISSN 1877-1173, 488pp".


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