Pathways connecting telomeres and p53 in senescence, apoptosis, and cancer

The ends of eukaryotic chromosomes are protected by specialized structures termed telomeres that serve in part to prevent the chromosome end from activating a DNA damage response. However, this important function for telomeres in chromosome end protection can be lost as telomeres shorten with cell division in culture or in self-renewing tissues with advancing age. Impaired telomere function leads to induction of a DNA damage response and activation of the tumor suppressor protein p53. p53 serves a critical role in enforcing both senescence and apoptotic responses to dysfunctional telomeres. Loss of p53 creates a permissive environment in which critically short telomeres are inappropriately joined to generate chromosomal end-to-end fusions. These fused chromosomes result in cycles of chromosome fusion-bridge-breakage, which can fuel cancer initiation, especially in epithelial tissues, by facilitating changes in gene copy number.     

Dyskeratosis congenita, telomeres and human ageing

As normal humans age, telomeres shorten in tissues that contain dividing cells, and this has been proposed both as a cause of ageing and as a tumor-suppressor mechanism. The surprising finding that cells from individuals with the rare inherited disorder dyskeratosis congenita (DKC) have reduced levels of telomerase and shortened telomeres might provide the first direct genetic test of the function of telomeres in intact humans.     

Increased p53 activity does not accelerate telomere-driven ageing

There is a great interest in determining the impact of p53 on ageing and, for this, it is important to discriminate among the known causes of ageing. Telomere loss is a well-established source of age-associated damage, which by itself can recapitulate ageing in mouse models. Here, we have used a genetic approach to interrogate whether p53 contributes to the elimination of telomere-damaged cells and its impact on telomere-driven ageing. We have generated compound mice carrying three functional copies of the p53 gene (super-p53) in a telomerase-deficient background and we have measured the presence of chromosomal abnormalities and DNA damage in several tissues. We have found that the in vivo load of telomere-derived chromosomal damage is significantly decreased in super-p53/telomerase-null mice compared with normal-p53/telomerase-null mice. Interestingly, the presence of extra p53 activity neither accelerates nor delays telomere-driven ageing. From these observations, we conclude that p53 has an active role in eliminating telomere-damaged cells, and we exclude the possibility of an age-promoting effect of p53 on telomere-driven ageing.     

Shorter telomeres, accelerated ageing and increased lymphoma in DNA-PKcs-deficient mice

Non-homologous end joining (NHEJ) is the principal repair mechanism used by mammalian cells to cope with double-strand breaks (DSBs) that continually occur in the genome. One of the key components of the mammalian NHEJ machinery is the DNA-PK complex, formed by the Ku86/70 heterodimer and the DNA-PK catalytic subunit (DNA-PKcs). Here, we report on the detailed life-long follow-up of DNA-PKcs-defective mice. Apart from defining a role of DNA-PKcs in telomere length maintenance in the context of the ageing organism, we observed that DNA-PKcs-defective mice had a shorter life span and showed an earlier onset of ageing-related pathologies than the corresponding wild-type littermates. In addition, DNA-PKcs ablation was associated with a markedly higher incidence of T lymphomas and infections. In conclusion, these data link the dual role of DNA-PKcs in DNA repair and telomere length maintenance to organismal ageing and cancer.     

p53转录非依赖活性介导细胞凋亡

p53主要通过两条途径诱导细胞凋亡：p53作为转录因子,促进细胞凋亡的靶基因的表达上调,如PUMA、NOXA、PIDD、p53AIP1、COP1等,并通过这些蛋白参与内源和外源凋亡途径;另一方面,胞浆中的p53能转位到线粒体,激活内源性的线粒体途径,促进凋亡。后者已成为研究p53促凋亡机制的热点。本文就p53对转录非依赖活性诱导细胞凋亡途径的研究进展作一概述。     

Mouse models with modified p53 sequences to study cancer and ageing

Experiments with p53 transgenic and p53 gene-targeted mouse strains have substantiated, and in some cases challenged, a number of hypotheses on the biology of the p53 protein. New questions have emerged regarding similarities and differences between murine and human genetic networks in various tissues. Mouse models with targeted p53 alleles are now applied not only to investigate tumour susceptibility, but also to address questions pertinent to molecular epidemiology, chemoprevention, development of anticancer p53-specific pharmaceuticals, and ageing.     

Living with p53, dying of p53

The p53 tumor suppressor protein acts as a major defense against cancer. Among its most distinctive features is the ability to elicit both apoptotic death and cell cycle arrest. In this issue of Cell, Das et al. (2007) and Tanaka et al. (2007) provide new insights into the mechanisms that dictate the life and death decisions of p53.     

Human mitochondria in health, disease, ageing and cancer

In every human cell there are hundreds of mitochondria, which are required for oxidative phosphorylation as well as many other metabolic processes. Each mitochondrion contains approximately 5 mitochondrial DNA molecules. These circular DNAs of 16.5 kb in size contain only 39 genes. Mutations in mitochondrial DNA are responsible for many diseases. Alterations in these molecules may also play a role in ageing and in tumour formation.     

p53DINP1, a p53-inducible gene, regulates p53-dependent apoptosis

Using the differential display method combined with a cell line that carries a well-controlled expression system for wild-type p53, we isolated a p53-inducible gene, termed p53DINP1 (p53-dependent damage-inducible nuclear protein 1). Cell death induced by DNA double-strand breaks (DSBs), as well as Ser46 phosphorylation of p53 and induction of p53AIP1, were blocked when we inhibited expression of p53DINP1 by means of an antisense oligonucleotide. Overexpression of p53DINP1 and DNA damage by DSBs synergistically enhanced Ser46 phosphorylation of p53, induction of p53AIP1 expression, and apoptotic cell death. Furthermore, the protein complex interacting with p53DINP1 was shown to phosphorylate Ser46 of p53. Our results suggest that p53DINP1 may regulate p53-dependent apoptosis through phosphorylation of p53 at Ser46, serving as a cofactor for the putative p53-Ser46 kinase.     

Quality control of mitochondria: protection against neurodegeneration and ageing

Dysfunction of mitochondria has severe cellular consequences and is linked to ageing and neurodegeneration in human. Several surveillance strategies have evolved that limit mitochondrial damage and ensure cellular integrity. Intraorganellar proteases conduct protein quality control and exert regulatory functions, membrane fusion and fission allow mitochondrial content mixing within a cell, and the autophagic degradation of severely damaged mitochondria protects against apoptosis. Here, we will summarize the current knowledge on these surveillance strategies and their role in human disease.