Nucleosomes specify co-factor access to p53
Date
2025
Authors
Chakraborty, D.
Sandate, C.R.
Isbel, L.
Kempf, G.
Weiss, J.
Cavadini, S.
Kater, L.
Seebacher, J.
Kozicka, Z.
Stoos, L.
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Journal article
Citation
Molecular Cell, 2025; 85(15):2919-2936.e12
Statement of Responsibility
Deyasini Chakraborty, Colby R. Sandate, Luke Isbel, Georg Kempf, Joscha Weiss, Simone Cavadini, Lukas Kater, Jan Seebacher, Zuzanna Kozicka, Lisa Stoos, Ralph S. Grand, Dirk Schübeler, Alicia K. Michael, Nicolas H. Thomä
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Abstract
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.
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© 2025 The Authors. Published by Elsevier Inc. 2919 This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).