Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 120, Issue 28, Pages -Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2302064120
Keywords
topoisomerase; chemotherapeutic; cancer; DNA damage; protein dynamics
Categories
Ask authors/readers for more resources
Type II topoisomerases temporarily cleave duplex DNA to control chromosomal organization, and mutations in hTOP2(3) can make the enzyme hypersensitive to the drug etoposide, leading to cell death. Some of these mutations are also found in cancer genome databases. These findings suggest a link between DNA cleavage predisposition and sensitivity to topoisomerase II poisons in cancer cells.
Type II topoisomerases transiently cleave duplex DNA as part of a strand passage mechanism that helps control chromosomal organization and superstructure. Aberrant DNA cleavage can result in genomic instability, and how topoisomerase activity is controlled to prevent unwanted breaks is poorly understood. Using a genetic screen, we identified mutations in the beta isoform of human topoisomerase II (hTOP2(3) that render the enzyme hypersensitive to the chemotherapeutic agent etoposide. Several of these variants were unexpectedly found to display hypercleavage behavior in vitro and to be capable of inducing cell lethality in a DNA repair-deficient background; surprisingly, a subset of these mutations were also observed in TOP2B sequences from cancer genome databases. Using molecular dynamics simulations and computational network analyses, we found that many of the mutations obtained from the screen map to interfacial points between structurally coupled elements, and that dynamical modeling could be used to identify other damage-inducing TOP2B alleles present in cancer genome databases. This work establishes that there is an innate link between DNA cleavage predisposition and sensitivity to topoisomerase II poisons, and that certain sequence variants of human type II topoisomerases found in cancer cells can act as DNA-damaging agents. Our findings underscore the potential for hTOP2(3 to function as a clastogen capable of generating DNA damage that may promote or support cellular transformation.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available