2025-07-31 スイス連邦工科大学ローザンヌ校(EPFL)
<関連情報>
- https://actu.epfl.ch/news/how-dna-packaging-controls-the-genome-s-guardian/
- https://www.cell.com/molecular-cell/fulltext/S1097-2765(25)00577-5
ヌクレオソームはp53への共因子のアクセスを規定する Nucleosomes specify co-factor access to p53
Deyasini Chakraborty ∙ Colby R. Sandate ∙ Luke Isbel ∙ … ∙ Dirk Schübeler ∙ Alicia K. Michael ∙ Nicolas H. Thomä
Molecular Cell Published:July 25, 2025
DOI:https://doi.org/10.1016/j.molcel.2025.06.027
Graphical abstract
Highlights
- Cryo-EM studies show p53-histone binding via DBD/TET at distinct nucleosome sites
- Biochemical and cryo-EM studies reveal full-length USP7-p53-nucleosome complex
- Deubiquitinating enzyme USP7 is active in the vicinity of chromatin-bound p53
- Cryo-EM shows that monomeric and dimeric E6AP-E6-p53 complex cannot bind nucleosome
Summary
Pioneer transcription factors (TFs) engage chromatinized DNA motifs. However, it is unclear how the resultant TF-nucleosome complexes are decoded by co-factors. In humans, the TF p53 regulates cell-cycle progression, apoptosis, and the DNA damage response, with a large fraction of p53-bound sites residing in nucleosome-harboring inaccessible chromatin. We examined the interaction of chromatin-bound p53 with co-factors belonging to the ubiquitin proteasome system (UPS). At two distinct motif locations on the nucleosome (super-helical location [SHL]-5.7 and SHL+5.9), the E3 ubiquitin ligase E6-E6AP was unable to bind nucleosome-engaged p53. The deubiquitinase USP7, on the other hand, readily engages nucleosome-bound p53 in vitro and in cells. A corresponding cryo-electron microscopy (cryo-EM) structure shows USP7 engaged with p53 and nucleosomes. Our work illustrates how chromatin imposes a co-factor-selective barrier for p53 interactors, whereby flexibly tethered interaction domains of co-factors and TFs govern compatibility between co-factors, TFs, and chromatin.
