This research program will apply the theoretical methods previously developed by this investigator to the analysis of strand separation in superhelical genomic DNA sequences. The strong associations previously found between sites of stress-induced duplex destabilization (SIDD) and specific types of regulatory regions will be investigated thoroughly. Many additional DNA sequences will be analyzed to determine the SIDD properties associated to transcriptionally active regions, replication origins, centromeres, mutational hotspots, chromosomal breakpoints and other sites of biological activity. The statistical significance of each association will be assessed. The present theoretical methods will be extended to treat the following cases not currently amenable to analysis: 1) long DNAs in which the topological coupling induced by superhelicity may be limited by nucleosomal winding, 2) duplex destabilization induced by the proximal binding of molecules such as transcription factors, 3) effects on transition behavior of local sequence modifications such as methylated or mispaired bases, or abasic sites, and 4) competitions between denaturation and other transitions to which specific local DNA sequences are susceptible, such as cruciform extrusion or transition to Z- or to H-form. Monte Carlo methods will be used to analyze the stabilization of B-form DNA at high temperatures by positive supercoiling. The existing collaboration with Dr. Richard Fye, which focuses on the development of theoretical methods to analyze DNA superhelical equilibria, will be continued. Collaborations with two experimental groups, will investigate the thermodynamics of superhelical DNA conformational transitions, and the roles they play in transcription.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
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Special Emphasis Panel (ZRG3-BBCA (01))
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Mount Sinai School of Medicine
Biostatistics & Other Math Sci
Schools of Medicine
New York
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Mielke, Christian; Christensen, Morten O; Westergaard, Ole et al. (2002) Multiple collagen I gene regulatory elements have sites of stress-induced DNA duplex destabilization and nuclear scaffold/matrix association potential. J Cell Biochem 84:484-96
Benham, Craig J; Savitt, Anne G; Bauer, William R (2002) Extrusion of an imperfect palindrome to a cruciform in superhelical DNA: complete determination of energetics using a statistical mechanical model. J Mol Biol 316:563-81
Mistry, S J; Benham, C J; Atweh, G F (2001) Development of ribozymes that target stathmin, a major regulator of the mitotic spindle. Antisense Nucleic Acid Drug Dev 11:41-9
Moore, P B; Lopez, C F; Klein, M L (2001) Dynamical properties of a hydrated lipid bilayer from a multinanosecond molecular dynamics simulation. Biophys J 81:2484-94
Benham, C J (2001) Stress-induced DNA duplex destabilization in transcriptional initiation. Pac Symp Biocomput :103-14
Baiker, A; Maercker, C; Piechaczek, C et al. (2000) Mitotic stability of an episomal vector containing a human scaffold/matrix-attached region is provided by association with nuclear matrix. Nat Cell Biol 2:182-4
Leblanc, B P; Benham, C J; Clark, D J (2000) An initiation element in the yeast CUP1 promoter is recognized by RNA polymerase II in the absence of TATA box-binding protein if the DNA is negatively supercoiled. Proc Natl Acad Sci U S A 97:10745-50
Sheridan, S D; Benham, C J; Hatfield, G W (1999) Inhibition of DNA supercoiling-dependent transcriptional activation by a distant B-DNA to Z-DNA transition. J Biol Chem 274:8169-74
Sheridan, S D; Benham, C J; Hatfield, G W (1998) Activation of gene expression by a novel DNA structural transmission mechanism that requires supercoiling-induced DNA duplex destabilization in an upstream activating sequence. J Biol Chem 273:21298-308
Benham, C J (1996) Duplex destabilization in superhelical DNA is predicted to occur at specific transcriptional regulatory regions. J Mol Biol 255:425-34

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