All of the processes necessary for the survival of a living system hinge on its ability to store and read the genetic information encoded in its DNA. The packaging a long genome into the eukaryotic nucleus or prokaryotic nucleoid is complicated by the necessity of maintaining the accessibility of the DNA for genetic processing. The binding of multiple proteins to DNA plays an important role in reading and compacting the genome. Many regulatory proteins bind two or more widely separated sites along DNA, forcing the intervening sequence into a loop. Other architectural proteins deform the DNA at isolated sites of contact while concomitantly wrapping DNA on their surfaces. The complex interplay of DNA and these different types of proteins is one of the most exciting areas of contemporary biology. For example, the deletion of architectural proteins in E. coli cells perturbs the repression of genes controlled by the Lac repressor and chemical modifications of the histone proteins in eukaryotes, so-called epigenetic markers, affect a host of cellular processes. Although there is a large literature on protein- mediated DNA looping, there is no systematic understanding of how non-specific architectural proteins contribute to the formation of loops and how the structures of loop-mediating proteins like LacR control looping and gene repression. Several interrelated problems complicate the modeling of loops. First, the in vivo structures of both the bacterial nucleoid and chromatin are unknown. Second, since these loops contain too many constituents to be modeled at the atomic level, simplifications must be introduced. Third, popular approaches used to model DNA looping have important deficiencies. To address these needs, we propose to (i) establish methodologies to model long, protein-decorated DNA chains at a 'realistic'level and characterize the topology of the simulated structures, (ii) establish the role of architectural and regulatory proteins found in the bacterial nucleoid on the spatial organization and expression of genes, and (iii) establish the role of nucleosome structure and deformation on the organization and expression of genes in a model system. Aside from the fundamental importance to an understanding of biology, knowledge of the interplay between local and large-scale biomolecular structure and genetic function could transform life-science technologies. That is, if certain environmental pressures perturb genomic structure and switch genes on or off, then perhaps one might be able to engineer such changes in an organism and correct diseased states or optimize production of desired products.

Public Health Relevance

The proposed studies of DNA in the presence of multiple proteins will extend our knowledge of how the three-dimensional packaging of DNA in the cells of different organisms contributes to the processing of genetic information. Aside from fundamental understanding of biology, this information has the potential to transform life-science technologies. That is, if certain environmental pressures perturb genomic structure and switch genes on or off, then perhaps one might be able to engineer such changes in an organism and correct diseased states or optimize production of desired products.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM034809-28
Application #
8732660
Study Section
Macromolecular Structure and Function D Study Section (MSFD)
Program Officer
Preusch, Peter
Project Start
1985-08-01
Project End
2015-08-31
Budget Start
2014-09-01
Budget End
2015-08-31
Support Year
28
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Rutgers University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
City
New Brunswick
State
NJ
Country
United States
Zip Code
08901
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Yusufaly, Tahir I; Li, Yun; Singh, Gautam et al. (2014) Arginine-phosphate salt bridges between histones and DNA: intermolecular actuators that control nucleosome architecture. J Chem Phys 141:165102
Wei, Juan; Czapla, Luke; Grosner, Michael A et al. (2014) DNA topology confers sequence specificity to nonspecific architectural proteins. Proc Natl Acad Sci U S A 111:16742-7
Perez, Pamela J; Clauvelin, Nicolas; Grosner, Michael A et al. (2014) What controls DNA looping? Int J Mol Sci 15:15090-108
Clauvelin, Nicolas; Olson, Wilma K; Tobias, Irwin (2014) Effect of the boundary conditions and influence of the rotational inertia on the vibrational modes of an elastic ring. J Elast 115:193-224
Yusufaly, Tahir I; Li, Yun; Olson, Wilma K (2013) 5-Methylation of cytosine in CG:CG base-pair steps: a physicochemical mechanism for the epigenetic control of DNA nanomechanics. J Phys Chem B 117:16436-42
Olson, Wilma K; Grosner, Michael A; Czapla, Luke et al. (2013) Structural insights into the role of architectural proteins in DNA looping deduced from computer simulations. Biochem Soc Trans 41:559-64
Czapla, Luke; Grosner, Michael A; Swigon, David et al. (2013) Interplay of protein and DNA structure revealed in simulations of the lac operon. PLoS One 8:e56548
Colasanti, Andrew V; Grosner, Michael A; Perez, Pamela J et al. (2013) Weak operator binding enhances simulated Lac repressor-mediated DNA looping. Biopolymers 99:1070-81

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