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PXD008293

PXD008293 is an original dataset announced via ProteomeXchange.

Dataset Summary
TitleHistone deacetylase inhibitors mediate selective degradation of nuclear uracil-DNA glycosylase 2 and increased genomic uracil
DescriptionHDAC inhibitors (HDACi) belong to a new group of chemotherapeutics that are increasingly used to treat B-cell-derived malignancies. Such malignancies regularly carry mutational signatures that conform to off-target induction of uracil by the AID/APOBEC family of cytidine deaminases, or downstream processing of uracil. . HDACi suppress thymidylate synthase increasing the cellular dUTP/dTTP ratio and leading to increased pressure on uracil repair machinery due to misincorporated uracil lesions. To investigate potential effect upon other enzymes involved in genomic uracil induction and processing, Jurkat (T-cell lymphoma) and SUDHL5 (B-cell lymphoma) cells were treated with pan-HDACi SAHA prior to SILAC based MS/MS investigation. HDACi treatment mediated significant differential expression of xx and xx proteins in Jurkat and SUDHL5, respectively, and had a substantial impact upon enzymes involved in in pyrimidine metabolism. Surprisingly, uracil N-glycosylase, UNG, was strongly downregulated by HDACi treatment. Further analysis in HEK and HeLa cells revealed that HDACis induce specific loss of the nuclear isoform UNG2 independent of transcription and cell-cycle alterations. More than 80% of UNG2 is degraded proteasomally after 24 hours treatment with SAHA, MS275, Valproate or Na-butyrate, indicating a universal ability of HDACis to mediate loss of UNG2. Targeted MS/MS analysis in HEK cells against a panel of proteins involved in DNA repair, translesion synthesis and nucleotide metabolism, revealed that UNG2 was the most pronounced differentially expressed among these after HDACi treatment. 48 hour treatment lead to a 30-40% increase in uracil lesions in the nuclear genome of HeLa and HEK cells and MS275 treatment in murine CH12F3 cell line mediated robust UNG2-loss accompanied by reduced class switch recombination. Furthermore, our analysis identified the PCNA-associated factor PAF15 among the downregulated proteins. PAF15 is overexpressed in many cancers and suppress TLS by inducing double monoubiquitinylation of PCNA and recruitment of the replicative polymerases. In summary, our findings demonstrate that HDAC inhibition affects the levels of proteins involved in DNA base excision repair, translesion synthesis and pyrimidine metabolism. These findings are important for a wide range of clinical applications of HDACi, such as in rheumatology, HIV-, and cancer treatment.
HostingRepositoryPRIDE
AnnounceDate2020-04-14
AnnouncementXMLSubmission_2020-04-13_22:48:31.xml
DigitalObjectIdentifier
ReviewLevelPeer-reviewed dataset
DatasetOriginOriginal dataset
RepositorySupportUnsupported dataset by repository
PrimarySubmitterAnimesh Sharma
SpeciesList scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationListacetylated residue
InstrumentQ Exactive
Dataset History
RevisionDatetimeStatusChangeLog Entry
02017-11-24 05:25:28ID requested
12020-04-13 22:48:32announced
Publication List
Iveland TS, Hagen L, Sharma A, Sousa MML, Sarno A, Wollen KL, Liabakk NB, Slupphaug G, HDACi mediate UNG2 depletion, dysregulated genomic uracil and altered expression of oncoproteins and tumor suppressors in B- and T-cell lines. J Transl Med, 18(1):159(2020) [pubmed]
Keyword List
curator keyword: Biological
submitter keyword: AA, amino acid
AID, activation induced deaminase;
Contact List
Geir Slupphaug
contact affiliationProfessor i molekylærbiologi og faglig leder av PROMEC Institutt for klinisk og molekylær medisin Erling Skjalgssons g 1, aboratoriesenteret * * Laboratoriesenter Norwegian University of Science and Technology Trondheim 7030 Norway ( lab head )
contact emailgeir.slupphaug@ntnu.no
lab head
Animesh Sharma
contact affiliationEngineer at NTNU, Norway
contact emailsharma.animesh@gmail.com
dataset submitter
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