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

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

Author information

1
Genome Integrity and Structural Biology Laboratory, National Institute of Environmental Health Sciences (NIEHS), Research Triangle Park, NC 27709, USA.
2
Centro Andaluz de Biología Molecular y Medicina Regenerativa (CABIMER), CSIC-Universidad de Sevilla Universidad Pablo de Olavide, 41092 Sevilla, Spain.
3
Epigenetics and Stem Cell Biology Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.
4
Centro Andaluz de Biología Molecular y Medicina Regenerativa (CABIMER), CSIC-Universidad de Sevilla Universidad Pablo de Olavide, 41092 Sevilla, Spain. felipe.cortes@cabimer.es williamsrs@niehs.nih.gov.
5
Genome Integrity and Structural Biology Laboratory, National Institute of Environmental Health Sciences (NIEHS), Research Triangle Park, NC 27709, USA. felipe.cortes@cabimer.es williamsrs@niehs.nih.gov.

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.

PMID:
28912134
PMCID:
PMC5623066
[Available on 2018-09-29]
DOI:
10.1126/science.aam6468
[Indexed for MEDLINE]

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