Curaxin-Induced DNA Topology Alterations Trigger the Distinct Binding Response of CTCF and FACT at the Single-Molecule Level.

Affiliation

Lu K(1)(2), Liu C(3), Liu Y(1), Luo A(4), Chen J(4), Lei Z(5), Kong J(1)(2), Xiao X(1)(2), Zhang S(1)(6), Wang YZ(7), Ma L(1), Dou SX(1)(2), Wang PY(1)(2)(8), Li M(1)(2)(8), Li G(3)(2), Li W(1)(8), Chen P(4)(3).
Author information:
(1)National Laboratory for Condensed Matter Physics and Key Laboratory of Soft Matter Physics, Institute of Physics, Chinese Academy of Sciences, Beijing 100190, China.
(2)University of Chinese Academy of Sciences, Beijing 100049, China.
(3)National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
(4)Department of Immunology, School of Basic Medical Sciences, Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing 100069, China.
(5)State Key Laboratory of Physical Chemistry of Solid Surfaces, Department of Chemistry, College of Chemistry and Chemical Engineering, and iChEM, Xiamen University, Xiamen 361005, China.
(6)Key Laboratory of Environment and Female Reproductive Health, West China School of Public Health & West China Fourth Hospital, Sichuan University, Chengdu 610041, China.
(7)Genome Analysis Laboratory of the Ministry of Agriculture, Agricultural Synthetic Biology Center, Agricultural Genomics Institute at Shenzhen, Chinese Academy of Agricultural Sciences, Shenzhen, Guangdong 518124, China.
(8)Songshan Lake Materials Laboratory, Dongguan, Guangdong 523808, China.

Abstract

The candidate anticancer drug curaxins can insert into DNA base pairs and efficiently inhibit the growth of various cancers. However, how curaxins alter the genomic DNA structure and affect the DNA binding property of key proteins remains to be clarified. Here, we first showed that curaxin CBL0137 strongly stabilizes the interaction between the double strands of DNA and reduces DNA bending and twist rigidity simultaneously, by single-molecule magnetic tweezers. More importantly, we found that CBL0137 greatly impairs the binding of CTCF but facilitates trapping FACT on DNA. We revealed that CBL0137 clamps the DNA double helix that may induce a huge barrier for DNA unzipping during replication and transcription and causes the distinct binding response of CTCF and FACT on DNA. Our work provides a novel mechanical insight into CBL0137's anticancer mechanisms at the nucleic acid level.