Folding/unfolding kinetics of G-quadruplexes upstream of the P1 promoter of the human BCL-2 oncogene.

The Journal of Biological Chemistry
Yuanlei ChengHuijuan You

Abstract

The G-rich Pu39 region of the P1 promoter of the oncogene BCL-2, an apoptosis regulator, can fold into multiple G-quadruplex (G4) structures. Bcl2-2345 and Bcl2-1245 are two major G4 species forming with high thermal stability and distinct topologies in the Pu39 region, but their folding/unfolding kinetics have not yet been investigated. Here, we used magnetic tweezers to measure the mechanical stability and the folding/unfolding kinetics of the Bcl2-2345 and Bcl2-1245 G4 structures. We report that the hybrid-stranded Bcl2-2345 G4 had a lower mechanical stability than the parallel-stranded Bcl2-1245 G4. We observed that the Bcl2-2345 G4 is a kinetically favored structure, whereas the Bcl2-1245 G4, with a slow unfolding rate, may function as a kinetic barrier for transcription. We also determined that in addition to the Bcl2-2345 and Bcl2-1245 G4s, other stable DNA secondary structures, such as a hybrid-stranded Bcl2-1234 G4, can also form in the Pu39 sequence. The characterization of the folding/unfolding kinetics of specific G4s reported here sheds light on the participation of G4s during gene transcription and provides information for designing G4-targeting small molecules that could modulate BCL-2 gene expression.

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Citations

Apr 18, 2019·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Dora M RăsădeanG Dan Pantoș
Apr 14, 2021·Nucleic Acids Research·Enrico BuglioneFrancesco Mantegazza
May 20, 2021·Nucleic Acids Research·Phong Lan Thao TranVincent Croquette
Jul 25, 2021·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Antonino LauriaAnnamaria Martorana
Sep 5, 2020·The Journal of Physical Chemistry Letters·Yuanlei ChengHuijuan You
Aug 31, 2021·Cellular and Molecular Life Sciences : CMLS·Fang-Yuan TengYong Xu

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