Faculty Opinions recommendation of ZATT (ZNF451)-mediated resolution of topoisomerase 2 DNA-protein cross-links.
Year: 2019
Type: peer-review
Abstract: Topoisomerase 2 (TOP2) DNA transactions are essential for life, and 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 crosslinks are resolved is unclear.Here, we show that the SUMO 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 SUMO2modulated pathway for direct resolution of TOP2cc.Topoisomerase 2 (TOP2α and TOP2β in mammalian cells) regulates DNA topology through the production of a transient DNA double strand breaks (1).The key intermediate in the TOP2 reaction is the covalent protein-DNA TOP2 cleavage complex (TOP2cc), a protein-
Author: Scott Kaufmann
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
Awards: G1735476216, G2123841078, Global dynamics of topoisomerase-induced DNA breaks, G3825695467, Nmr Studies Of Biomolecular Structure, Function, And Dynamics, MINOS (Macromolecular Insights on Nucleic acids Optimized by Scattering), G7345354777, G7453307320, G7559664950, G9000043759, G9000299002
OpenAlex ID: W4239334564