Effect of TDP2 on the Level of TOP2-DNA Complexes and SUMOylated TOP2-DNA Complexes

International Journal of Molecular Sciences
Ka Cheong LeeCaroline A Austin

Abstract

DNA topoisomerase II (TOP2) activity involves a normally transient double-strand break intermediate in which the enzyme is coupled to DNA via a 5'-phosphotyrosyl bond. However, etoposide and other topoisomerase drugs poison the enzyme by stabilising this enzyme-bridged break, resulting in the accumulation of TOP2-DNA covalent complexes with cytotoxic consequences. The phosphotyrosyl diesterase TDP2 appears to be required for efficient repair of this unusual type of DNA damage and can remove 5'-tyrosine adducts from a double-stranded oligonucleotide substrate. Here, we adapt the trapped in agarose DNA immunostaining (TARDIS) assay to investigate the role of TDP2 in the removal of TOP2-DNA complexes in vitro and in cells. We report that TDP2 alone does not remove TOP2-DNA complexes from genomic DNA in vitro and that depletion of TDP2 in cells does not slow the removal of TOP2-DNA complexes. Thus, if TDP2 is involved in repairing TOP2 adducts, there must be one or more prior steps in which the protein-DNA complex is processed before TDP2 removes the remaining 5' tyrosine DNA adducts. While this is partly achieved through the degradation of TOP2 adducts by the proteasome, a proteasome-independent mechanism has also been described i...Continue Reading

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Citations

Sep 14, 2019·Molecular Pharmacology·Ian G CowellCaroline A Austin
Jun 27, 2020·Molecular Pharmacology·Rebecca L SwanCaroline A Austin
Nov 16, 2019·Cellular and Molecular Life Sciences : CMLS·Amanda A RiccioR Scott Williams
Oct 9, 2020·Cancers·Caroline MolinaroKatia Cailliau
May 5, 2021·Molecular Pharmacology·Rebecca L SwanCaroline A Austin
Oct 25, 2021·Molecular Pharmacology·Rebecca L SwanCaroline A Austin

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Methods Mentioned

BETA
TARDIS
ICE

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