Transcription elongation factor SPT5 (SPT5)

Transcription elongation factor SPT5 (encoded by the SUPT5H gene) is a highly conserved protein that, together with SPT4, forms the DRB sensitivity-inducing factor (DSIF) complex. This complex is a central regulator of RNA polymerase II (Pol II) transcription, playing dual roles in both promoting promoter-proximal pausing and facilitating productive elongation. SPT5 also coordinates co-transcriptional events such as mRNA capping, splicing, and 3' end processing, and it is essential for maintaining the stability of the Pol II complex by preventing the degradation of its largest subunit, RPB1. In clinical contexts, SPT5 is a significant therapeutic target due to its role in transcribing MYC-driven oncogenes in various cancers and its involvement in the expression of mutant huntingtin in Huntington's disease. Additionally, it is a critical host factor for HIV-1 replication, where it facilitates Tat-mediated transcriptional transactivation. While small-molecule inhibitors (SPIs) are being developed to selectively target SPT5-dependent transcription, the protein's essential role in global gene expression presents a major challenge for achieving a favorable therapeutic index.

Other names

SUPT5HhSPT5DSIF p160DRB sensitivity-inducing factor 160 kDa subunitDRB sensitivity-inducing factor large subunitTat-cotransactivator 1 proteinTat-CT1Suppressor of Ty 5 homolog

Inhibition of the SPT5-RNA polymerase II interaction or DSIF complex activity to prevent transcriptional elongation of specific target genes and induce promoter-proximal pausing.