PXD022351

PXD022351 is an original dataset announced via ProteomeXchange.

Title	Inhibition of tryptophan 2,3-dioxygenase impairs DNA damage tolerance and repair in glioma cells
Description	Expression of tryptophan 2,3-dioxygenase (TDO) is a determinant of malignancy in gliomas through kynurenine (KYN) signaling. We report that inhibition of TDO activity attenuated recovery from replication stress and increased the genotoxic effects of bis-chloroethylnitrosourea (BCNU). Activation of the Chk1 arm of the replication stress response (RSR) was reduced when TDO activity was blocked prior to BCNU treatment, whereas phosphorylation of serine 33 (pS33) on replication protein A (RPA) was enhanced - indicative of increased fork collapse. Analysis of quantitative proteomic results revealed TDO-dependent changes in several pathways - including down-regulation of 53BP1 and sirtuin signaling. We went on to show that cells lacking TDO activity exhibited defective recruitment of 53BP1 to gamma-H2AX foci, which corresponded with delayed repair of DNA breaks. Addition of exogenous KYN increased the rate of break repair. TDO inhibition diminished SIRT7 deacetylase recruitment to chromatin, which increased histone H3K18 acetylation - a key mark involved in preventing 53BP1 recruitment to sites of DNA damage. These results highlight the potential for tumor-specific metabolic changes to influence genome stability and may have implications for glioma treatment strategies.
HostingRepository	PRIDE
AnnounceDate	2021-09-09
AnnouncementXML	Submission_2021-09-09_13:14:02.948.xml
DigitalObjectIdentifier	https://dx.doi.org/10.6019/PXD022351
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	Stephanie Byrum
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2020-11-04 07:29:25	ID requested
⏵ 1	2021-09-09 13:14:03	announced

Reed MR, Maddukuri L, Ketkar A, Byrum SD, Zafar MK, Bostian ACL, Tackett AJ, Eoff RL, Inhibition of tryptophan 2,3-dioxygenase impairs DNA damage tolerance and repair in glioma cells. NAR Cancer, 3(2):zcab014(2021) [pubmed]

submitter keyword: DNA damage, DNA replication, DNA repair, kynurenine, replication stress, tryptophan 2,3-dioxygenase

Robert L. Eoff
contact affiliation	Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, U.S.A
contact email	RLEoff@uams.edu
lab head
Stephanie Byrum
contact affiliation	UAMS
contact email	sbyrum@uams.edu
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD022351
     1. Label: PRIDE project
     2. Name: Inhibition of tryptophan 2,3-dioxygenase impairs DNA damage tolerance and repair in glioma cells