Locally acting transcription factors regulate p53-dependent cis-regulatory element activity

Catizone, Allison N; Uzunbas, Gizem Karsli; Celadova, Petra; Kuang, Sylvia; Bose, Daniel; Sammons, Morgan A.

doi:10.1093/nar/gkaa147

Cited by 22 publications

(23 citation statements)

References 81 publications

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“…It is now appreciated that even though p53 seems to be able to regulate its target genes without cooperating with additional sequence-specific TFs ( 93 , 94 ), they can nonetheless contribute to p53-dependent transcriptional activation at some genomic binding sites ( 95 ). We suggest that the effect of nearby yeast cis-regulatory elements, and the TFs that bind them, may be an answer to the question of the significantly higher transactivation levels from RLminus relative to those from other p21-5′ variants studied here, when its binding characteristics (measured and predicted) are not different from those of the other variants.…”

Section: Discussionmentioning

confidence: 99%

The complex architecture of p53 binding sites

Senitzki

Safieh

Sharma

et al. 2021

Nucleic Acids Research

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Sequence-specific protein-DNA interactions are at the heart of the response of the tumor-suppressor p53 to numerous physiological and stress-related signals. Large variability has been previously reported in p53 binding to and transactivating from p53 response elements (REs) due, at least in part, to changes in direct (base) and indirect (shape) readouts of p53 REs. Here, we dissect p53 REs to decipher the mechanism by which p53 optimizes this highly regulated variable level of interaction with its DNA binding sites. We show that hemi-specific binding is more prevalent in p53 REs than previously envisioned. We reveal that sequences flanking the REs modulate p53 binding and activity and show that these effects extend to 4–5 bp from the REs. Moreover, we show here that the arrangement of p53 half-sites within its REs, relative to transcription direction, has been fine-tuned by selection pressure to optimize and regulate the response levels from p53 REs. This directionality in the REs arrangement is at least partly encoded in the structural properties of the REs. Furthermore, we show here that in the p21-5′ RE the orientation of the half-sites is such that the effect of the flanking sequences is minimized and we discuss its advantages.

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Section: Discussionmentioning

confidence: 99%

The complex architecture of p53 binding sites

Senitzki

Safieh

Sharma

et al. 2021

Nucleic Acids Research

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“…Another MPRA approach provided additional evidence for the role of other TFs in regulating p53 transcriptional activity. ( 149 ). Screening the transcriptional activity of thousands of variants of p53-bound regulatory elements revealed that other motifs flanking a p53RE contribute to p53-dependent activation.…”

Section: Functional Consequences Of P53 Binding In Varied Genomic Conmentioning

confidence: 99%

“…Screening the transcriptional activity of thousands of variants of p53-bound regulatory elements revealed that other motifs flanking a p53RE contribute to p53-dependent activation. One such example was binding of ATF3 and p53 to an enhancer element regulating expression of GDF15 ( 149 ). ATF3 and p53 have been previously shown to co-occupy many genomic locations, with ATF3 activity contributing to p53-dependent activation of numerous downstream targets ( 63 , 150 ).…”

Section: Functional Consequences Of P53 Binding In Varied Genomic Conmentioning

confidence: 99%

Tumor suppressor p53: from engaging DNA to target gene regulation

Sammons

Nguyen

McDade

et al. 2020

Nucleic Acids Research

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The p53 transcription factor confers its potent tumor suppressor functions primarily through the regulation of a large network of target genes. The recent explosion of next generation sequencing protocols has enabled the study of the p53 gene regulatory network (GRN) and underlying mechanisms at an unprecedented depth and scale, helping us to understand precisely how p53 controls gene regulation. Here, we discuss our current understanding of where and how p53 binds to DNA and chromatin, its pioneer-like role, and how this affects gene regulation. We provide an overview of the p53 GRN and the direct and indirect mechanisms through which p53 affects gene regulation. In particular, we focus on delineating the ubiquitous and cell type-specific network of regulatory elements that p53 engages; reviewing our understanding of how, where, and when p53 binds to DNA and the mechanisms through which these events regulate transcription. Finally, we discuss the evolution of the p53 GRN and how recent work has revealed remarkable differences between vertebrates, which are of particular importance to cancer researchers using mouse models.

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“…p53 is a common tumor suppressor that controls the transcription of extensive gene networks involved in apoptosis, cell cycle arrest, DNA damage repair, and aging[ 54 ]. Physiological p53 activity can prevent cancer and aging, while unrestricted and excessive p53 activity can promote aging [ 5 ].…”

Section: Molecular Mechanisms Of Cellular Senescence and Saspmentioning

confidence: 99%

Cellular Senescence Affects Cardiac Regeneration and Repair in Ischemic Heart Disease

Yan¹,

Xu²,

Huang³

2021

Aging and disease

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Ischemic heart disease (IHD) is defined as a syndrome of ischemic cardiomyopathy. Myogenesis and angiogenesis in the ischemic myocardium are important for cardiomyocyte (CM) survival, improving cardiac function and decreasing the progression of heart failure after IHD. Cellular senescence is a state of permanent irreversible cell cycle arrest caused by stress that results in a decline in cellular functions, such as proliferation, migration, homing, and differentiation. In addition, senescent cells produce the senescence-associated secretory phenotype (SASP), which affects the tissue microenvironment and surrounding cells by secreting proinflammatory cytokines, chemokines, growth factors, and extracellular matrix degradation proteins. The accumulation of cardiovascular-related senescent cells, including vascular endothelial cells (VECs), vascular smooth muscle cells (VSMCs), CMs and progenitor cells, is an important risk factor of cardiovascular diseases, such as vascular aging, atherosclerotic plaque formation, myocardial infarction (MI) and ventricular remodeling. This review summarizes the processes of angiogenesis, myogenesis and cellular senescence after IHD. In addition, this review focuses on the relationship between cellular senescence and cardiovascular disease and the mechanism of cellular senescence. Finally, we discuss a potential therapeutic strategy for MI targeting senescent cells.

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Locally acting transcription factors regulate p53-dependent cis-regulatory element activity

Cited by 22 publications

References 81 publications

The complex architecture of p53 binding sites

The complex architecture of p53 binding sites

Tumor suppressor p53: from engaging DNA to target gene regulation

Cellular Senescence Affects Cardiac Regeneration and Repair in Ischemic Heart Disease

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