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Biochemical and Biophysical Study of the Polymorphic G-Quadruplexes Formed by the Insulin Linked Polymorphic Region

Schonhoft, Joseph
http://rave.ohiolink.edu/etdc/view?acc_num=kent1248116483

Abstract Details

2009, MS, Kent State University, College of Arts and Sciences / Department of Chemistry.
The Insulin Linked Polymorphic Region (ILPR) is a VNTR region located upstream of the Insulin (INS) gene that consists of the repeat 5′-ACAGGGGTGTGGGG (repeat a) and several less abundant sequence repeats (repeats b-n). Repeats in the ILPR have been shown to have the ability to adopt a non B-DNA conformation known as a G-quadruplex, consisting of planar stacks of Hoogsteen hydrogen bonded guanine nucleotides. Here, we have investigated the structural polymorphism of G-quadruplexes formed from the most common repeat sequences and have discovered several unique thermodynamic and kinetic properties. Specifically, the repeats can adopt many different G-quadruplex topologies and the predominant repeat ‘a’ can form two distinct conformations that coexist in solution. We have also shown that tandem G-quadruplexes can interact to form a quadruplex inspired higher order structure, which is one of the first of such observations, and strongly suggests that conformations adopted by multiple G-quadruplexes in tandem cannot always be predicted from the structure of a single unit. Additionally, previous research has shown that the protein Insulin can bind the ILPR G-quadruplex formed from the repeat ‘a’, raising the intriguing possibility that Insulin may be directly involved in its own self-regulation. Here we have shown that the protein Insulin can interact specifically with the predominant G-quadruplex formed from the repeat ‘a’ over other ILPR G-quadruplexes, and that the loop nucleotides of the G-quadruplex play a decisive role in the G-quadruplex conformation, which directly determines Insulin affinity. Collectively, this study will aid in learning more about the ILPR’s mechanism of sequence polymorphism as well as lay the ground work towards explaining its effect on Insulin transcription and the ILPR’s role in type I diabetes. Furthermore, the work here provides additional evidence to the understanding of G-quadruplex polymorphism in general, which will be essential in reaching a more complete understanding of the complexities of biological regulation by these unique DNA structures.
Soumitra Basu, PhD (Advisor)
Frederick Walz, PhD (Committee Member)
Hanbin Mao, PhD (Committee Member)
180 p.
Biochemistry
G-quadruplex; ILPR

Recommended Citations

Citations

  • Schonhoft, J. (2009). Biochemical and Biophysical Study of the Polymorphic G-Quadruplexes Formed by the Insulin Linked Polymorphic Region [Master's thesis, Kent State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=kent1248116483

    APA Style (7th edition)

  • Schonhoft, Joseph. Biochemical and Biophysical Study of the Polymorphic G-Quadruplexes Formed by the Insulin Linked Polymorphic Region. 2009. Kent State University, Master's thesis. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=kent1248116483.

    MLA Style (8th edition)

  • Schonhoft, Joseph. "Biochemical and Biophysical Study of the Polymorphic G-Quadruplexes Formed by the Insulin Linked Polymorphic Region." Master's thesis, Kent State University, 2009. http://rave.ohiolink.edu/etdc/view?acc_num=kent1248116483

    Chicago Manual of Style (17th edition)

kent1248116483
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© 2009, all rights reserved.
This open access ETD is published by Kent State University and OhioLINK.