ZATT (ZNF451)-mediated resolution of topoisomerase 2 DNA-protein cross-links

Science. 2017 Sep 29;357(6358):1412-1416. doi: 10.1126/science.aam6468. Epub 2017 Sep 14.

Abstract

Topoisomerase 2 (TOP2) DNA transactions proceed via formation of the TOP2 cleavage complex (TOP2cc), a covalent enzyme-DNA reaction intermediate that is vulnerable to trapping by potent anticancer TOP2 drugs. How genotoxic TOP2 DNA-protein cross-links are resolved is unclear. We found that the SUMO (small ubiquitin-related modifier) ligase ZATT (ZNF451) is a multifunctional DNA repair factor that controls cellular responses to TOP2 damage. ZATT binding to TOP2cc facilitates a proteasome-independent tyrosyl-DNA phosphodiesterase 2 (TDP2) hydrolase activity on stalled TOP2cc. The ZATT SUMO ligase activity further promotes TDP2 interactions with SUMOylated TOP2, regulating efficient TDP2 recruitment through a "split-SIM" SUMO2 engagement platform. These findings uncover a ZATT-TDP2-catalyzed and SUMO2-modulated pathway for direct resolution of TOP2cc.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Aminoacyltransferases
  • Animals
  • Bacterial Proteins / genetics
  • Bacterial Proteins / metabolism
  • Biocatalysis
  • Catalytic Domain
  • DNA / genetics
  • DNA / metabolism
  • DNA Damage*
  • DNA Repair*
  • DNA Topoisomerases, Type II / genetics
  • DNA Topoisomerases, Type II / metabolism*
  • DNA-Binding Proteins
  • Etoposide / pharmacology
  • Gene Knockdown Techniques
  • HEK293 Cells
  • Humans
  • Immunoprecipitation
  • Luminescent Proteins / genetics
  • Luminescent Proteins / metabolism
  • Mice
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Phosphoric Diester Hydrolases
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Saccharomyces cerevisiae Proteins / genetics
  • Saccharomyces cerevisiae Proteins / metabolism
  • Small Ubiquitin-Related Modifier Proteins / metabolism
  • Sumoylation
  • Topoisomerase II Inhibitors / pharmacology
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / metabolism

Substances

  • Bacterial Proteins
  • DNA-Binding Proteins
  • Luminescent Proteins
  • Nuclear Proteins
  • Recombinant Proteins
  • SUMO2 protein, human
  • Saccharomyces cerevisiae Proteins
  • Small Ubiquitin-Related Modifier Proteins
  • Topoisomerase II Inhibitors
  • Transcription Factors
  • yellow fluorescent protein, Bacteria
  • Etoposide
  • DNA
  • Aminoacyltransferases
  • ZNF451 protein, human
  • ZNF451 protein, mouse
  • Ubiquitin-Protein Ligases
  • Phosphoric Diester Hydrolases
  • TDP2 protein, human
  • DNA Topoisomerases, Type II