HIF-1 Interacts with TRIM28 and DNA-PK to release paused RNA polymerase II and activate target gene transcription in response to hypoxia

• Published in: Nature communications Vol. 13; no. 1; p. 316
• Main Authors: Yang, Yongkang, Lu, Haiquan, Chen, Chelsey, Lyu, Yajing, Cole, Robert N, Semenza, Gregg L
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 14.01.2022; Nature Publishing Group UK; Nature Portfolio
• Subjects: Amino Acid Motifs; Anticancer properties; Availability; Binding; Breast cancer; Cell Line, Tumor; Cyclin-Dependent Kinase 9 - genetics; Cyclin-Dependent Kinase 9 - metabolism; Deoxyribonucleic acid; DNA; DNA-Activated Protein Kinase - genetics; DNA-Activated Protein Kinase - metabolism; DNA-dependent protein kinase; DNA-directed RNA polymerase; Drug delivery; Elongation; Gene expression; Gene Expression Regulation; Genes; Homeostasis; Humans; Hypoxia; Hypoxia - genetics; Hypoxia - metabolism; Hypoxia-inducible factor 1; Hypoxia-Inducible Factor 1 - genetics; Hypoxia-Inducible Factor 1 - metabolism; Hypoxia-inducible factor 1a; Kinases; Nucleotides; Oxygen; Phosphorylation; Promoter Regions, Genetic; Protein Binding; Proteins; Recruitment; Regulatory sequences; Response Elements; Ribonucleic acid; RNA; RNA polymerase; RNA polymerase II; RNA Polymerase II - chemistry; RNA Polymerase II - genetics; RNA Polymerase II - metabolism; Serine; Transcription factors; Transcription, Genetic; Tripartite Motif-Containing Protein 28 - genetics; Tripartite Motif-Containing Protein 28 - metabolism
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-27944-8

Hypoxia-inducible factor-1 (HIF-1) is a transcription factor that acts as a regulator of oxygen (O ) homeostasis in metazoan species by binding to hypoxia response elements (HREs) and activating the transcription of hundreds of genes in response to reduced O availability. RNA polymerase II (Pol II) initiates transcription of many HIF target genes under non-hypoxic conditions but pauses after approximately 30-60 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 as well as the negative elongation factor to release paused Pol II, thereby stimulating productive transcriptional elongation. Our studies reveal a molecular mechanism by which HIF-1 stimulates gene transcription and reveal that the anticancer effects of drugs targeting DNA-PK in breast cancer may be due in part to their inhibition of HIF-dependent transcription.