Abstract

The sequence specific recognition of double helical DNA is an essential biological process responsible for the regulation of cellular functions including transcription, replication, and cell division. The ability to design synthetic molecules that bind sequence specifically to unique sites on human DNA has major implications for the treatment of genetic, oncogenic and viral diseases. Basic research on structure-function issues such as recognition and covalent modification of DNA and RNA will be carried out. Research will focus on peptide recognition of the minor groove of double helical DNA, cleavage studies of DNA by designed metalloproteins, and the development of new affinity cleaving methods for studying RNA structure and RNA-ligand interactions. Our specific objectives during the next five years are: (1) recognition of mixed sequence DNA in the minor groove by dimeric peptide analogs, (2) studies of the oxidative cleavage of DNA in the minor groove by Ni(II)GGH(Hin 139-190), (3) design of synthetic hybrid metalloproteins for sequence specific oxidative cleavage of DNA in the minor groove, (4) a general method for mapping higher order RNA structures, (5) affinity cleavage of protein-RNA complexes.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM027681-13
Application #
3274905
Study Section
Bio-Organic and Natural Products Chemistry Study Section (BNP)
Project Start
1980-04-01
Project End
1995-11-30
Budget Start
1992-12-01
Budget End
1993-11-30
Support Year
13
Fiscal Year
1993
Total Cost
Indirect Cost

  Institution

Name
California Institute of Technology
Department
Type
Schools of Engineering
DUNS #
078731668
City
Pasadena
State
CA
Country
United States
Zip Code
91125

  Publications

Kurmis, Alexis A; Yang, Fei; Welch, Timothy R et al. (2017) A Pyrrole-Imidazole Polyamide Is Active against Enzalutamide-Resistant Prostate Cancer. Cancer Res 77:2207-2212
Xu, Jun; Lahiri, Indrajit; Wang, Wei et al. (2017) Structural basis for the initiation of eukaryotic transcription-coupled DNA repair. Nature 551:653-657
Mysore, Veena S; Szablowski, Jerzy; Dervan, Peter B et al. (2016) A DNA-binding Molecule Targeting the Adaptive Hypoxic Response in Multiple Myeloma Has Potent Antitumor Activity. Mol Cancer Res 14:253-66
Xu, Liang; Wang, Wei; Gotte, Deanna et al. (2016) RNA polymerase II senses obstruction in the DNA minor groove via a conserved sensor motif. Proc Natl Acad Sci U S A 113:12426-12431
Szablowski, Jerzy O; Raskatov, Jevgenij A; Dervan, Peter B (2016) An HRE-Binding Py-Im Polyamide Impairs Hypoxic Signaling in Tumors. Mol Cancer Ther 15:608-17
Kang, JeenJoo S; Dervan, Peter B (2015) A sequence-specific DNA binding small molecule triggers the release of immunogenic signals and phagocytosis in a model of B-cell lymphoma. Q Rev Biophys 48:453-64
Hargrove, Amanda E; Martinez, Thomas F; Hare, Alissa A et al. (2015) Tumor Repression of VCaP Xenografts by a Pyrrole-Imidazole Polyamide. PLoS One 10:e0143161
Martínez, Thomas F; Phillips, John W; Karanja, Kenneth K et al. (2014) Replication stress by Py-Im polyamides induces a non-canonical ATR-dependent checkpoint response. Nucleic Acids Res 42:11546-59
Raskatov, Jevgenij A; Puckett, James W; Dervan, Peter B (2014) A C-14 labeled Py-Im polyamide localizes to a subcutaneous prostate cancer tumor. Bioorg Med Chem 22:4371-5
Kang, JeenJoo S; Meier, Jordan L; Dervan, Peter B (2014) Design of sequence-specific DNA binding molecules for DNA methyltransferase inhibition. J Am Chem Soc 136:3687-94

Showing the most recent 10 out of 77 publications