Distinct mechanisms control genome recognition by p53 at its target genes linked to different cell fates.

Authors

Marina Farkas, Thomas Jefferson UniversityFollow
Hideharu Hashimoto, Thomas Jefferson UniversityFollow
Yingtao Bi, Northwestern University
Ramana V Davuluri, Northwestern University
Lois Resnick-Silverman, Icahn School of Medicine at Mount Sinai
James J. Manfredi, Icahn School of Medicine at Mount Sinai
Erik W. Debler, Thomas Jefferson UniversityFollow
Steven B. McMahon, Thomas Jefferson UniversityFollow

Document Type

Article

Publication Date

1-20-2021

Comments

This article is the author’s final published version in Nature Communications, Volume 12, Issue 1, December 2020, Article number 484.

The published version is available at https://doi.org/10.1038/s41467-020-20783-z. Copyright © Farkas et al.

Publication made possible in part by support from the Jefferson Open Access Fund

Abstract

The tumor suppressor p53 integrates stress response pathways by selectively engaging one of several potential transcriptomes, thereby triggering cell fate decisions (e.g., cell cycle arrest, apoptosis). Foundational to this process is the binding of tetrameric p53 to 20-bp response elements (REs) in the genome (RRRCWWGYYYN_0-13RRRCWWGYYY). In general, REs at cell cycle arrest targets (e.g. p21) are of higher affinity than those at apoptosis targets (e.g., BAX). However, the RE sequence code underlying selectivity remains undeciphered. Here, we identify molecular mechanisms mediating p53 binding to high- and low-affinity REs by showing that key determinants of the code are embedded in the DNA shape. We further demonstrate that differences in minor/major groove widths, encoded by G/C or A/T bp content at positions 3, 8, 13, and 18 in the RE, determine distinct p53 DNA-binding modes by inducing different Arg248 and Lys120 conformations and interactions. The predictive capacity of this code was confirmed in vivo using genome editing at the BAX RE to interconvert the DNA-binding modes, transcription pattern, and cell fate outcome.

Recommended Citation

Farkas, Marina; Hashimoto, Hideharu; Bi, Yingtao; Davuluri, Ramana V; Resnick-Silverman, Lois; Manfredi, James J.; Debler, Erik W.; and McMahon, Steven B., "Distinct mechanisms control genome recognition by p53 at its target genes linked to different cell fates." (2021). Department of Biochemistry and Molecular Biology Faculty Papers. Paper 176.
https://jdc.jefferson.edu/bmpfp/176

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 License.

PubMed ID

33473123

Language

English