| HSF1 is the master heat shock transcription factor that senses proteotoxic and other stresses and switches on a broad cytoprotective transcriptional program, while also engaging additional pathways controlling RNA processing, genome maintenance, and oncogenic growth. The protein contains an N‑terminal winged helix–turn–helix DNA‑binding domain, adjacent hydrophobic heptad repeats that mediate stress‑inducible trimerization, a regulatory region harboring multiple phosphorylation, acetylation, and sumoylation sites, and a C‑terminal transactivation domain that recruits co‑activators to chromatin. Under non‑stress conditions HSF1 resides in a multichaperone complex with HSP90 and other heat shock proteins that maintains it as an inert monomer with low DNA‑binding activity; accumulation of misfolded proteins during heat or other stresses titrates away chaperones, allowing HSF1 trimerization, acquisition of high‑affinity binding to inverted 5′‑NGAAN‑3′ pentamers in heat shock elements, and assembly with TTC5/STRAP and p300/EP300 at HSP gene promoters. Activated HSF1 stimulates transcription of a large set of chaperones and proteostasis regulators, but also directly upregulates FOXR1, which then induces HSPA1A, HSPA6, and the antioxidant enzyme DHRS2, extending the heat shock response to include additional chaperones and redox control. HSF1 also promotes efficient expression of HSP70 by enhancing pre‑mRNA 3′‑end processing and polyadenylation in a SYMPK‑dependent manner and by facilitating nuclear export of stress‑induced HSP70 mRNA, linking promoter binding to downstream RNA maturation and trafficking steps. HSF1 also interacts directly with the DNA double‑strand break repair proteins Ku70 and Ku86 at their N‑terminal regions, competes with Ku70–Ku80 heterodimer formation after ionizing radiation, and thereby inhibits classical non‑homologous end joining independently of its transcriptional activity, leading to reduced NHEJ efficiency and increased genomic instability when HSF1 is highly expressed. In tumor contexts, HSF1 is frequently overexpressed and constitutively activated, and a p53 target gene, IER5, forms a complex with HSF1 and PP2A that promotes dephosphorylation of multiple serine and threonine residues to generate a hypo‑phosphorylated active HSF1 species; IER5 is upregulated from a super‑enhancer–associated locus in several cancers and drives abnormal HSF1 activation that supports proliferation of stressed cancer cells. HSF1 also binds directly to the HIV‑1 LTR, recruits p300 and p‑TEFb (CDK9–cyclin T1), and enhances transcriptional elongation from latent proviruses, so HSF1 activity is a positive determinant of HIV‑1 gene expression and latency reversal in infected cells. |
