GTF2H4

GTF2H4 (p52) is an essential subunit of the TFIIH core complex required for nucleotide excision repair and RNA polymerase II transcription, established through its yeast ortholog Tfb2 whose C-terminal truncation abolishes NER and confers UV sensitivity (PMID:9235928). Its central architectural role is to anchor the XPB/Ssl2 DNA translocase within TFIIH: residues of the C-terminal HubA region are required for stable Ssl2/XPB incorporation, and HubA mutations reduce TFIIH and pol II promoter occupancy and impair gene induction, with the Tfb6 factor genetically modulating Ssl2 dissociation (PMID:36041630). The same C-terminal region directly and selectively contacts the accessory NER subunit Tfb5/p8 — an interaction resolved at atomic resolution and functionally required for efficient repair — thereby bridging the XPB helicase to Tfb5; this domain also binds nucleic acids, and Tfb5 binding displaces the bound nucleic acid (PMID:17215295, PMID:19897425, PMID:20606254). Beyond its core transcription/repair role, GTF2H4 acts in endothelial cells as a positive regulator of partial endothelial-to-mesenchymal transition under ischemic conditions, where, together with ERCC3, it promotes NCOA3 phosphorylation at serine 1330 to enhance NCOA3–p65 interaction and NF-κB/Snail signaling (PMID:38379791).

1. 1997 High

   Established that the p52 subunit is an essential TFIIH component whose C-terminus is specifically required for NER, defining its functional importance and the human-yeast orthology.

   Evidence Yeast deletion/truncation genetics with UV sensitivity and cell-extract NER complementation by purified TFIIH, plus sequence alignment to human p52

   PMID:9235928

   Open questions at the time

   • Did not resolve which TFIIH interactions the C-terminus mediates
   • No structural or biochemical mechanism for the repair defect
2. 2007 High

   Identified a direct, selective Tfb2/p52 contact with the accessory subunit Tfb5/p8, localizing the repair-critical function to a specific interaction interface.

   Evidence Co-IP, domain deletion mapping, and UV/NER complementation in yeast extracts

   PMID:17215295

   Open questions at the time

   • Structural basis of the interface unknown
   • Effect on XPB/Ssl2 not addressed
3. 2009 Medium

   Showed Tfb2/p52 functions as a bridge linking the Ssl2/XPB helicase to Tfb5, and that the Tfb5-interacting domain binds nucleic acids in a manner reversed by Tfb5, hinting at a regulatory switch.

   Evidence Pulldown/co-IP, nucleic-acid binding assays, and genetic epistasis in yeast

   PMID:19897425

   Open questions at the time

   • Functional consequence of nucleic-acid displacement during NER not defined
   • Single-lab biochemistry
4. 2010 High

   Provided the atomic-resolution basis for the p52-p8 interaction, converting the genetic/biochemical interface into a defined structure.

   Evidence X-ray crystallography of Tfb5 with the Tfb2 C-terminal region at 1.7 Å

   PMID:20606254

   Open questions at the time

   • Structure of full-length p52 within intact TFIIH not resolved
   • Does not capture XPB-bound state
5. 2022 High

   Defined the HubA region as the determinant for stable XPB/Ssl2 incorporation into TFIIH and linked this to promoter occupancy and transcriptional activation, mechanistically connecting p52 architecture to function in both yeast and human cells.

   Evidence Systematic mutagenesis, XL-MS, cryo-EM, co-IP in yeast and human cells, ChIP, and gene expression assays

   PMID:36041630

   Open questions at the time

   • Role of Tfb6-equivalent regulation in human cells not established
   • Dynamics of Ssl2 association/dissociation during the catalytic cycle incomplete
6. 2024 Medium

   Extended GTF2H4 function beyond core transcription/repair to a signaling role in endothelial cells, identifying an NCOA3 phosphorylation event that drives NF-κB/Snail-mediated partial EndMT.

   Evidence Phosphoproteomics, site-directed mutagenesis, co-IP, and in vitro/in vivo ischemic injury loss/gain-of-function

   PMID:38379791

   Open questions at the time

   • Whether GTF2H4 directly phosphorylates NCOA3 or acts via an associated kinase is unresolved
   • Relationship between TFIIH core function and the EndMT role not mechanistically connected
   • Single-lab finding

• How GTF2H4's canonical TFIIH-scaffolding role mechanistically intersects with its context-specific EndMT signaling function remains unknown.
• No structure of human GTF2H4 in the EndMT signaling context
• Kinase responsible for NCOA3 S1330 phosphorylation unidentified