DNA dynamically directs its own transcription initiation.
It has long been known that double-stranded DNA is subject to temporary, localized openings of its two strands. Particular regions along a DNA polymer are destabilized structurally by available thermal energy in the system. The localized sequence of DNA determines the physical properties of a stretch of DNA, and that in turn determines the opening profile of that DNA fragment. We show that the Peyrard-Bishop nonlinear dynamical model of DNA, which has been used to simulate denaturation of short DNA fragments, gives an accurate representation of the instability profile of a defined sequence of DNA, as verified using S1 nuclease cleavage assays. By comparing results for a non-promoter DNA fragment, the adenovirus major late promoter, the adeno-associated viral P5 promoter and a known P5 mutant promoter that is inactive for transcription, we show that the predicted openings correlate almost exactly with the promoter transcriptional start sites and major regulatory sites. Physicists have speculated that localized melting of DNA might play a role in gene transcription and other processes. Our data link sequence-dependent opening behavior in DNA to transcriptional activity for the first time.
Endocrinology, Beth Israel Deaconess Medical Center and Harvard Medical School, Department of Medicine, 99 Brookline Avenue, Boston, MA 02215, USA.
Chu H
CH
Choi
George
G
Kalosakas
Kim O
KO
Rasmussen
Makoto
M
Hiromura
Alan R
AR
Bishop
Anny
A
Usheva
D000256:Adenoviridae / Q000235:genetics; D001483:Base Sequence; D003198:Computer Simulation; D004247:DNA / Q000737:chemistry*; D004277:DNA, Single-Stranded / Q000737:chemistry; D000229:Dependovirus / Q000235:genetics; D008969:Molecular Sequence Data; D009691:Nucleic Acid Denaturation; D011401:Promoter Regions, Genetic; D035581:Transcription Factor TFIIB / Q000235:genetics; D024363:Transcription Initiation Site; D014158:Transcription, Genetic
D004277:DNA, Single-Stranded; D035581:Transcription Factor TFIIB; D004247:DNA