PXD018549

PXD018549 is an original dataset announced via ProteomeXchange.

Title	Topoisomerase I Poisoning by Electrophiles Derived from Oxidative Stress
Description	The cancer target enyzme topoisomerase 1 transiently cleaves one strand of chromosomal DNA to relax accumulated strain that can prevent transcription, replication or chromatin assembly. The topoisomerase 1 poison camptothecin and its synthetic analogs are widely used chemotherapeutics that act by trapping the enzyme on DNA in a ‘covalent complex’, resulting in persistent DNA damage and cell death. The prevailing model, interfacial inhibition, contends that the covalent complex is trapped by drug binding alone. In contrast, here we show that camptothecins produce extensive oxidative stress and that topoisomerase 1 is reactive with electrophilic second messengers of oxidative damage. We show that blocking oxidative stress in cells inhibits covalent complex formation by camptothecin, while electrophiles such as 4-hydroxynonenal are able to induce covalent complex formation in cells on their own. Towards mechanism of action, we show that 4-hydroxynonenal electrophilically modifies a cysteine within the DNA-binding active site of human topoisomerase 1. Taken together, our results suggest a mechanism in which oxidative stress mediates the effects of many topoisomerase 1 poisons, and suggest that this critical DNA-regulating enzyme may have a dual role as a sensor of cellular redox stress, linking oxidative stress to DNA damage response in cancer cells.
HostingRepository	PRIDE
AnnounceDate	2024-10-22
AnnouncementXML	Submission_2024-10-22_05:20:19.315.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Donald Wolfgeher
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	formylated residue; monohydroxylated residue; deamidated residue
Instrument	Q Exactive HF

Revision	Datetime	Status	ChangeLog Entry
0	2020-04-14 07:56:39	ID requested
1	2021-03-24 12:39:12	announced
⏵ 2	2024-10-22 05:20:20	announced	2024-10-22: Updated project metadata.

10.1016/j.chembiol.2020.11.011;

Flor A, Wolfgeher D, Li J, Hanakahi LA, Kron SJ, Lipid-derived electrophiles mediate the effects of chemotherapeutic topoisomerase I poisons. Cell Chem Biol, 28(6):776-787.e8(2021) [pubmed]

submitter keyword: Oxidative Stress, Chemotherapy, Q-Exactive,Topoisomerases, Enzymology, Proteomics

Dr. Stephen Kron
contact affiliation	University of Chicago, Department of Molecular Genetics and Cell Biology, Chicago IL 60637, USA
contact email	skron@uchicago.edu
lab head
Donald Wolfgeher
contact affiliation	University of Chicago
contact email	donw@uchicago.edu
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD018549
     1. Label: PRIDE project
     2. Name: Topoisomerase I Poisoning by Electrophiles Derived from Oxidative Stress