SUPT5H encodes a component of the DRB sensitivity-inducing factor (DSIF) complex, which is essential for regulating RNA polymerase II (Pol II) transcription 1. As a multifunctional elongation factor, SUPT5H positively regulates mRNA capping by stimulating guanylyltransferase activity and acts cooperatively with the negative elongation factor complex (NELF) to enhance transcriptional pausing proximal to promoters, facilitating assembly of elongation-competent Pol II complexes 2. Following CDK9-mediated phosphorylation, SUPT5H switches to promote transcriptional elongation and is required for HIV-1 Tat-mediated transcription activation 1. SUPT5H depletion causes pronounced reduction of paused Pol II at promoters and enhancers with impaired transcription activation and Pol II processivity defects 1. Clinically, loss-of-function SUPT5H variants associate with β-thalassemia-like phenotypes in carriers, including elevated hemoglobin A2 levels 345. In breast cancer, SUPT5H is upregulated and interacts with PIN1 to promote tumorigenicity; SUPT5H depletion reduces proliferation and induces apoptosis 6. These findings establish SUPT5H as an essential positive regulator of global transcription with significant disease relevance in hemoglobinopathies and cancer.