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TEX264 coordinates p97- and SPRTN-mediated resolution of topoisomerase 1-DNA adducts by Fielden, John; Wiseman, Katherine; Torrecilla, Ignacio; Li, Shudong; Hume, Samuel; Chiang, Shih-Chieh; Ruggiano, Annamaria; Narayan Singh, Abhay; Freire, Raimundo; Hassanieh, Sylvana; Domingo, Enric; Vendrell, Iolanda; Fischer, Roman; Kessler, Benedikt M.; Maughan, Timothy S.; El-Khamisy, Sherif F.; Ramadan, Kristijan is a Biochemistry, Genetics and Molecular Biology article available to read on EtoBox.

What is TEX264 coordinates p97- and SPRTN-mediated resolution of topoisomerase 1-DNA adducts about?

Eukaryotic topoisomerase 1 (TOP1) regulates DNA topology to ensure efficient DNA replication and transcription. TOP1 is also a major driver of endogenous genome instability, particularly when its catalytic intermediate—a covalent TOP1-DNA adduct known as a TOP1 cleavage complex (TOP1cc)—is stabilised. TOP1ccs are highly cytotoxic and a failure to resolve them underlies the pathology of neurological disorders but is also exploited in cancer therapy where TOP1ccs are the target of widely used frontline anti-cancer drugs. A critical enzyme for TOP1cc resolution is the tyrosyl-DNA phosphodiesterase (TDP1), which hydrolyses the bond that links a tyrosine in the active site of TOP1 to a 3’ phosphate group on a single-stranded (ss)DNA break. However, TDP1 can only process small peptide fragments from ssDNA ends, raising the question of how the ~90 kDa TOP1 protein is processed upstream of TDP1. Here we find that TEX264 fulfils this role by forming a complex with the p97 ATPase and the SPRTN metalloprotease. We show that TEX264 recognises both unmodified and SUMO1-modifed TOP1 and initiates TOP1cc repair by recruiting p97 and SPRTN. TEX264 localises to the nuclear periphery, associates wit

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Author

Fielden, John; Wiseman, Katherine; Torrecilla, Ignacio; Li, Shudong; Hume, Samuel; Chiang, Shih-Chieh; Ruggiano, Annamaria; Narayan Singh, Abhay; Freire, Raimundo; Hassanieh, Sylvana; Domingo, Enric; Vendrell, Iolanda; Fischer, Roman; Kessler, Benedikt M.; Maughan, Timothy S.; El-Khamisy, Sherif F.; Ramadan, Kristijan

Publisher

Nature Publishing Group; Springer Science and Business Media LLC; [London]: Nature Publishing Group, 2010-; Society for Mining, Metallurgy and Exploration Inc.; Research Square (ISSN 2041-1723)

Published

2020

Language

EN

Field

Biochemistry, Genetics and Molecular Biology (Life Sciences)