PXD017239-1

PXD017239 is an original dataset announced via ProteomeXchange.

Title	TEX264 coordinates p97- and SPRTN-mediated resolution of topoisomerase 1-DNA adducts
Description	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. 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 TOP1ccs during DNA replication. Altogether, our study elucidates the existence of a specialised repair complex required for upstream proteolysis of TOP1ccs and their subsequent resolution.
HostingRepository	PRIDE
AnnounceDate	2024-10-07
AnnouncementXML	Submission_2024-10-07_10:35:19.390.xml
DigitalObjectIdentifier	https://dx.doi.org/10.6019/PXD017239
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	iolanda Vendrell
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	Oxidation; Acetyl; Carbamidomethyl
Instrument	Orbitrap Fusion Lumos; LTQ Orbitrap Velos

Revision	Datetime	Status	ChangeLog Entry
0	2020-01-21 08:24:08	ID requested
⏵ 1	2024-10-07 10:35:20	announced

10.1038/s41467-020-15000-w;

10.6019/PXD017239;

Fielden J, Wiseman K, Torrecilla I, Li S, Hume S, Chiang SC, Ruggiano A, Narayan Singh A, Freire R, Hassanieh S, Domingo E, Vendrell I, Fischer R, Kessler BM, Maughan TS, El-Khamisy SF, Ramadan K, TEX264 coordinates p97- and SPRTN-mediated resolution of topoisomerase 1-DNA adducts. Nat Commun, 11(1):1274(2020) [pubmed]

submitter keyword: protein-DNA adducts, VCP/p97, TOP1, TEX264,DNA repair, genome stability, SPRTN, DNA replication

Kristijan Ramadan
contact affiliation	Cancer Research UK and Medical Research Council Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford, OX3 7DQ, UK
contact email	kristijan.ramadan@oncology.ox.ac.uk
lab head
iolanda Vendrell
contact affiliation	CRUK-MRC Oxford Institute for Radiation Oncology, Oxford University
contact email	iolanda.vendrell@oncology.ox.ac.uk
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2020/03/PXD017239

PRIDE project URI

• PRIDE
  1. PXD017239
     1. Label: PRIDE project
     2. Name: TEX264 coordinates p97- and SPRTN-mediated resolution of topoisomerase 1-DNA adducts