TEX264 coordinates p97- and SPRTN-mediated resolution of topoisomerase 1-DNA adducts.

Nature Communications
John FieldenKristijan Ramadan

Abstract

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 with DNA replication forks, and counteracts TOP1cc...Continue Reading

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Citations

Apr 25, 2020·Environmental and Molecular Mutagenesis·Yusuke Kojima, Yuichi J Machida
Jan 6, 2021·Communications Biology·Annamaria Ruggiano, Kristijan Ramadan
Jan 30, 2021·Trends in Biochemical Sciences·Susan Ferro-NovickJeffrey L Brodsky
Feb 19, 2021·Matrix Biology : Journal of the International Society for Matrix Biology·Thomas Juretschke, Petra Beli
Mar 18, 2021·Autophagy·John FieldenKristijan Ramadan
Jul 13, 2020·DNA Repair·Guido Zagnoli-Vieira, Keith W Caldecott
Mar 12, 2021·Nucleic Acids Research·Mohamed Elsaid Ashour, Nima Mosammaparast
May 7, 2021·Biochimica Et Biophysica Acta. Proteins and Proteomics·Xiaoying WeiKun Yang
May 5, 2021·Molecular Pharmacology·Rebecca L SwanCaroline A Austin
Oct 5, 2021·Current Protocols·John L NitissNancy Maizels

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Datasets Mentioned

BETA
PXD017239

Methods Mentioned

BETA
co-immunoprecipitation
pulldown
pulldowns
tandem-affinity purifications
tandem affinity purifications
electrophoretic mobility shift assay
electrophoresis
transfections
FACS
PCR

Software Mentioned

SPRTN
Phyre2
Andor Komet7
Bio
FlowJo
ImageJ
ClearView
iPOND
[UNK]
GraphPad Prism

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