The Guardian of the Genome Revisited: p53 Downregulates Genes Required for Telomere Maintenance, DNA Repair, and Centromere Structure.

Eléonore Toufektchan,Franck Toledo

doi:10.3390/cancers10050135

Abstract

The p53 protein has been extensively studied for its capacity to prevent proliferation of cells with a damaged genome. Surprisingly, however, our recent analysis of mice expressing a hyperactive mutant p53 that lacks the C-terminal domain revealed that increased p53 activity may alter genome maintenance. We showed that p53 downregulates genes essential for telomere metabolism, DNA repair, and centromere structure and that a sustained p53 activity leads to phenotypic traits associated with dyskeratosis congenita and Fanconi anemia. This downregulation is largely conserved in human cells, which suggests that our findings could be relevant to better understand processes involved in bone marrow failure as well as aging and tumor suppression.

Highlights

First identified in complex with the SV40 tumor-virus oncoprotein [1,2,3,4], p53 was initially described as an oncogene [4,5]
We discuss the insights gained from our recent analyses of mice expressing p53∆31, which is a mutant protein that lacks the C-terminal domain [36]. This mouse model exhibited increased p53 activity, which demonstrates that the p53 C-terminus plays a negative regulatory role on the protein. It revealed that increased p53 activity may alter the genome through the downregulation of genes involved in telomere maintenance, DNA repair, and centromere structure, and lead to the development of phenotypic traits associated with bone marrow failure syndromes
Rtel1, which is one of the three genes mutated in dyskeratosis congenita (DC) and repressed by p53, encodes a Fancj-like helicase while Blm and Fen1, two other genes we found downregulated by p53, respectively, encode a helicase and an endonuclease that interact with Fanc proteins

Summary

Introduction

First identified in complex with the SV40 tumor-virus oncoprotein [1,2,3,4], p53 was initially described as an oncogene [4,5]. Cancers 2018, 10, 0135 found in human cancers (known as hot-spot mutations) are localized within this core domain [31] These mutations mainly act by disrupting p53 capacity to bind DNA or by altering the folding of the domain. We discuss the insights gained from our recent analyses of mice expressing p53∆31 , which is a mutant protein that lacks the C-terminal domain [36]. This mouse model exhibited increased p53 activity, which demonstrates that the p53 C-terminus plays a negative regulatory role on the protein. It revealed that increased p53 activity may alter the genome through the downregulation of genes involved in telomere maintenance, DNA repair, and centromere structure, and lead to the development of phenotypic traits associated with bone marrow failure syndromes

Removing the p53 C-Terminal Domain Leads to p53 Activation

Implications for Our Understanding of Pediatric and Developmental Syndromes

Implications for Our Understanding of Aging Processes

Conclusions