Mechanistic understanding of living things requires our understanding of how proteins and DNA interact together to generate functional chromosomes. This understanding is central to preserving human health, dealing with genetic disorders, and fighting pathogenic organisms. The proposed projects are focused on single-molecule analyses which permit direct visualization of biomolecule interactions, and can be used to analyze protein-DNA interactions in detail.
The aims of the proposal include careful study of an "exchange" mechanism for removal of proteins from DNA that suggests a major revision of conventional descriptions of protein turnover on DNA, and which will affect a wide range of studies of gene regulatory and chromosome-structural proteins.
A second aim i s focused on direct study of mechanisms of large "Structural Maintenance of chromosomes" protein complexes which mediate the folding of chromosomes in eukaryote cells. Finally, a third aim is focused on mechanisms underlying a family of "cut and paste" DNA recombination systems responsible in part for generating bacteria genetic diversity. The highly mechanistic analyses of DNA-processing machinery that are proposed will give us a stronger understanding of how cells interpret, fold and change their genomes, leading to a better understanding of pathologies where those functions are impaired, and better understanding of how to target those functions in pathogenic organisms.

Public Health Relevance

All genetic processes are ultimately controlled by protein-DNA interactions. Incorrect processing of DNA in humans lead to a wide range of genetic disorders, while induction of errors in DNA processing provides a strategy to control pathogenic organisms. The proposed project seeks to obtain mechanistic understanding of proteins that interact with DNA and thereby to advance our ability to control genetic processes.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM105847-02
Application #
8735170
Study Section
Macromolecular Structure and Function C Study Section (MSFC)
Program Officer
Lewis, Catherine D
Project Start
2013-09-30
Project End
2017-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
2
Fiscal Year
2014
Total Cost
$258,985
Indirect Cost
$78,985
Name
Northwestern University at Chicago
Department
Biochemistry
Type
Schools of Arts and Sciences
DUNS #
160079455
City
Evanston
State
IL
Country
United States
Zip Code
60201
Sing, Charles E; Olvera de la Cruz, Monica; Marko, John F (2014) Multiple-binding-site mechanism explains concentration-dependent unbinding rates of DNA-binding proteins. Nucleic Acids Res 42:3783-91
Pederson, Thoru; Marko, John F (2014) Nuclear physics (of the cell, not the atom). Mol Biol Cell 25:3466-9
Banigan, Edward J; Marko, John F (2014) Torque correlation length and stochastic twist dynamics of DNA. Phys Rev E Stat Nonlin Soft Matter Phys 89:062706