PXD024373

PXD024373 is an original dataset announced via ProteomeXchange.

Title	Screening HIF-1 Cofactors in Breast Cancer Cells by RIME
Description	Hypoxia-inducible factor-1 (HIF-1) is a transcription factor that acts as a master regulator of oxygen homeostasis in metazoan species by binding to hypoxia response elements (HREs) and activating the transcription of hundreds of genes in response to reduced O2 availability. RNA polymerase II (Pol II) initiates transcription of many HIF target genes under non-hypoxic conditions, but pauses after 20-100 nucleotides and requires HIF-1 binding for release. Here we report that in hypoxic breast cancer cells, HIF-1 recruits TRIM28 and DNA-dependent protein kinase (DNA-PK) to HREs to release paused Pol II. We show that HIF-1α and TRIM28 assemble the catalytically-active DNA-PK heterotrimer, which phosphorylates TRIM28 at serine-824, enabling recruitment of CDK9, which phosphorylates serine-2 of the Pol II large subunit C-terminal domain and the negative elongation factor to release paused Pol II, thereby stimulating productive transcriptional elongation. Our studies have revealed a critical molecular mechanism by which HIF-1 stimulates gene transcription and suggest that the anticancer effects of drugs targeting DNA-PK in breast cancer may be due in part to their inhibition of HIF-dependent transcription.
HostingRepository	PRIDE
AnnounceDate	2022-02-17
AnnouncementXML	Submission_2022-02-16_16:01:12.902.xml
DigitalObjectIdentifier	https://dx.doi.org/10.6019/PXD024373
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	Chelsey Chen
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	monohydroxylated residue; iodoacetamide derivatized residue; deamidated residue
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2021-02-24 21:59:53	ID requested
⏵ 1	2022-02-16 16:01:13	announced

Yang Y, Lu H, Chen C, Lyu Y, Cole RN, Semenza GL, HIF-1 Interacts with TRIM28 and DNA-PK to release paused RNA polymerase II and activate target gene transcription in response to hypoxia. Nat Commun, 13(1):316(2022) [pubmed]

submitter keyword: Human, Breast Cancer, HIF-1, RIME

Gregg Leonard Semenza
contact affiliation	Institute for Cell Engineering, Sidney Kimmel Comprehensive Cancer Center, Department of Biological Chemistry, McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University School of Medicine, USA
contact email	gsemenza@jhmi.edu
lab head
Chelsey Chen
contact affiliation	Johns Hopkins University
contact email	cchen223@jhu.edu
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD024373
     1. Label: PRIDE project
     2. Name: Screening HIF-1 Cofactors in Breast Cancer Cells by RIME