Molecular mechanisms of topoisomerase 2 DNA-protein crosslink resolution

Cell Mol Life Sci. 2020 Jan;77(1):81-91. doi: 10.1007/s00018-019-03367-z. Epub 2019 Nov 15.

Abstract

The compaction of DNA and the continuous action of DNA transactions, including transcription and DNA replication, create complex DNA topologies that require Type IIA Topoisomerases, which resolve DNA topological strain and control genome dynamics. The human TOP2 enzymes catalyze their reactions via formation of a reversible covalent enzyme DNA-protein crosslink, the TOP2 cleavage complex (TOP2cc). Spurious interactions of TOP2 with DNA damage, environmental toxicants and chemotherapeutic "poisons" perturbs the TOP2 reaction cycle, leading to an accumulation of DNA-protein crosslinks, and ultimately, genomic instability and cell death. Emerging evidence shows that TOP2-DNA protein crosslink (DPC) repair entails multiple strand break repair activities, such as removal of the poisoned TOP2 protein and rejoining of the DNA ends through homologous recombination (HR) or non-homologous end joining (NHEJ). Herein, we discuss the molecular mechanisms of TOP2-DPC resolution, with specific emphasis on the recently uncovered ZATTZnf451-licensed TDP2-catalyzed TOP2-DPC reversal mechanism.

Keywords: Chemotherapeutics; DNA strand breaks; Structural biology; TOP2; Tdp2; Topoisomerase 2; Tyrosyl DNA phosphodiesterase 2; ZATT; ZNF451.

Publication types

  • Review

MeSH terms

  • Aminoacyltransferases / chemistry
  • Aminoacyltransferases / metabolism
  • Animals
  • DNA / chemistry
  • DNA / genetics
  • DNA / metabolism*
  • DNA Breaks*
  • DNA Repair*
  • DNA Topoisomerases, Type II / chemistry
  • DNA Topoisomerases, Type II / metabolism*
  • Humans
  • Poly-ADP-Ribose Binding Proteins / chemistry
  • Poly-ADP-Ribose Binding Proteins / metabolism*
  • Protein Conformation
  • Sumoylation
  • Transcription Factors / chemistry
  • Transcription Factors / metabolism

Substances

  • Poly-ADP-Ribose Binding Proteins
  • Transcription Factors
  • DNA
  • Aminoacyltransferases
  • ZNF451 protein, human
  • DNA Topoisomerases, Type II
  • TOP2A protein, human