Normal telomere length and chromosomal end capping in poly(ADP-ribose) polymerase–deficient mice and primary cells despite increased chromosomal instability
TL;DR: The results presented here indicate that PARp-1 does not play a major role in regulating telomere length or in telomeric end capping, and the chromosomal instability of PARP-1−/− primary cells can be explained by the repair defect associated to PARP -1 deficiency.
Abstract: Poly(ADP-ribose) polymerase (PARP)-1, a detector of single-strand breaks, plays a key role in the cellular response to DNA damage. PARP-1-deficient mice are hypersensitive to genotoxic agents and display genomic instability due to a DNA repair defect in the base excision repair pathway. A previous report suggested that PARP-1-deficient mice also had a severe telomeric dysfunction consisting of telomere shortening and increased end-to-end fusions (d'Adda di Fagagna, F., M.P. Hande, W.-M. Tong, P.M. Lansdorp, Z.-Q. Wang, and S.P. Jackson. 1999. NAT: Genet. 23:76-80). In contrast to that, and using a panoply of techniques, including quantitative telomeric (Q)-FISH, we did not find significant differences in telomere length between wild-type and PARP-1(-/)- littermate mice or PARP-1(-/)- primary cells. Similarly, there were no differences in the length of the G-strand overhang. Q-FISH and spectral karyotyping analyses of primary PARP-1(-/)- cells showed a frequency of 2 end-to-end fusions per 100 metaphases, much lower than that described previously (d'Adda di Fagagna et al., 1999). This low frequency of end-to-end fusions in PARP-1(-/)- primary cells is accordant with the absence of severe proliferative defects in PARP-1(-/)- mice. The results presented here indicate that PARP-1 does not play a major role in regulating telomere length or in telomeric end capping, and the chromosomal instability of PARP-1(-/)- primary cells can be explained by the repair defect associated to PARP-1 deficiency. Finally, no interaction between PARP-1 and the telomerase reverse transcriptase subunit, Tert, was found using the two-hybrid assay.
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TL;DR: Current knowledge concerning the role of PARPs in establishment and inheritance of heterochromatic structures is described, and how their contribution affects biological outcomes is highlighted.
Abstract: Poly(ADP-ribose) polymerases (PARPs) are enzymes that transfer poly(ADP-ribose) (PAR) groups to target proteins, and thereby affect various nuclear and cytoplasmic processes. The activity of PARP family members, such as PARP1 and PARP2, is tied to cellular signalling pathways, and, through poly(ADP-ribosyl)ation, they ultimately promote changes in chromatin architecture, gene expression, and the location and activity of proteins that mediate signalling responses. A growing body of evidence suggest that PARPs, particularly PARP1 and PARP2, also operate at heterochromatic regions such as the inactive X chromosome, telomeres, pericentric heterochromatin and silent ribosomal RNA (rRNA) genes. Both proteins localize to heterochromatic sites and often associate with or poly(ADP-ribosyl)ate histones and heterochromatin-binding proteins, thereby modulating their activities. In this review, we describe current knowledge concerning the role of PARPs in establishment and inheritance of heterochromatic structures, and highlight how their contribution affects biological outcomes.
53 citations
TL;DR: The data suggest that there could be an accelerated telomere dysfunction in lymphocytes of Alzheimer disease patients, which induces the increase of telomerase activity and the decrease of proliferation activity of lymphocytes, and subsequently results in the impairment of immune function in Alzheimer disease Patients.
Abstract: Objective: The objective of this study was to investigate the telomerase activity of phytohemagglutinin-activated lymphocytes from patients with Alzheimer disease. Background: There is impairment of immune function in patients with Alzheimer disease, and the perturbation of immune system is Involved the pathogenesis of Alzheimer disease. However, the mechanism of the impairment is unclear so far. Methods: We analyzed telomerase activities of phytohemag-glutinin-activated lymphocytes from 187 cases of patients with Alzheimer disease, 53 cases of patients with vascular dementia, and 80 cases of age-matched healthy controls, respectively. Telomerase activity was measured using the telomeric repeat amplification protocol-based telomerase polymerase chain reaction enzyme-linked immunosorbent assay. We also detected the proliferation activity of peripheral blood mononuclear cells from 10 cases of patients with Alzheimer disease or 10 cases of age-matched healthy controls by [ 3 H] thymidine incorporation. Results: Telomerase activity of phytohemagglutinin-activated lymphocytes in Alzheimer disease patients was significantly elevated compared with healthy controls (P < 0.01) and vascular dementia patients (P < 0.01), respectively. There was significant statistical correlation between the telomerase activities of lymphocytes and the degree of dementia in Alzheimer disease patients. The proliferation activity of peripheral blood mononuclear cells to phytohemagglutinin was significantly decreased in Alzheimer disease patients compared with age-matched healthy controls (P < 0.01). Conclusions: Our data suggest that there could be an accelerated telomere dysfunction in lymphocytes of Alzheimer disease patients, which induces the increase of telomerase activity and the decrease of proliferation activity of lymphocytes, and subsequently results in the impairment of immune function in Alzheimer disease patients.
52 citations
Cites background from "Normal telomere length and chromoso..."
...sions and single-stranded DNA breaks, which also cause severe telomeric dysfunction.(21) But telomeric dysfunction must give rise to...
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TL;DR: The evidence that telomeres and the molecular pathways of telomere maintenance can play a role in determining the outcome of radiation exposure is now substantial and the field of telitere biology deserves continued attention from radiobiologists.
Abstract: Purpose : To review the basic features of telomeres with particular emphasis on their potential importance in radiation biology. Recent findings suggest that telomere length can influence radiation sensitivity in mouse and that several human radiosensitive disorders also show abnormalities in telomere dynamics. Numerous studies indicate that telomeric sequences may play a role in determining the stability of certain genomic regions both spontaneously and following irradiation. Furthermore, a number of transmissible genomic instability systems have been described in which it appears that telomere metabolism may be contributing to the delayed effects observed. Features of telomeres and telomere biology relevant to these topics are reviewed. Conclusions : The evidence that telomeres and the molecular pathways of telomere maintenance can play a role in determining the outcome of radiation exposure is now substantial. Thus, the field of telomere biology deserves continued attention from radiobiologists.
47 citations
Cites background from "Normal telomere length and chromoso..."
...The capping (Samper et al. 2001) ; accordingly, adult PARP-1-de cient mice do not express any severepresence of this pathway coincides with the presence of a novel nuclear body, the ALT-associated promyel- phenotype....
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TL;DR: It is shown that ARTD1–/– mice fed an HFD display impaired adipogenesis and show exacerbated hepatic steatosis, which can have important implications for nonalcoholic fatty liver disease.
Abstract: ADP-ribosyltransferase Diphtheria toxin-like 1 [ARTD1; formerly called poly-ADP-ribose polymerase 1 (PARP1)] is a chromatin-associated enzyme involved in regulating metabolic homeostasis. The liver is at the core of glucose and lipid metabolism and is significantly affected by obesity and the metabolic syndrome. Here, we show that when fed a high-fat diet (HFD), mice lacking ARTD1 developed exacerbated hepatic steatosis. ARTD1(-/-) mice had a 19% higher liver weight than wild-type (WT) animals and exhibited a significantly increased serum concentration of cholesterol (38%) and impaired glucose tolerance. In addition, adipocyte function and size were significantly reduced in ARTD1(-/-) mice fed an HFD (7794 μm(2) for WT and 5579 μm(2) for ARTD1(-/-) mice). The significantly reduced adipogenic differentiation of adipose-derived stromal cells (ASCs) isolated from ARTD1(-/-) mice (28 vs. 11% Oil red O-positive cells in WT and ARTD1(-/-) ASCs, respectively) suggested that impaired adipogenesis as the underlying cause for this adipose tissue malfunction. This function of ARTD1 was specific for adipogenesis, since osteogenic differentiation was not affected by the ARTD1 deletion. In summary, we show that ARTD1(-/-) mice fed an HFD display impaired adipogenesis and show exacerbated hepatic steatosis, which can have important implications for nonalcoholic fatty liver disease.
45 citations
TL;DR: Evidence is found for an association of the PARP‐1 V 762A polymorphism with increased risk of cancer among Asians, but decreased risk ofcancer among Caucasians, particularly of glioma.
Abstract: Poly(ADP-ribose) polymerase-1 (PARP-1 catalyzes poly(ADP-ribosyl)ation to various proteins involved in many cellular processes, including DNA damage detection and repair and cell proliferation and death. PARP-1 has been implicated in human carcinogenesis, but the association between the most-studied PARP-1 V762A polymorphism (rs1136410) and risk of various cancers was reported with inconclusive results. The aim of this study was to assess the association between the PARP-1 V762A polymorphism and cancer risk. A meta-analysis of 21 studies with 12,027 cancer patients and 14,106 cancer-free controls was conducted to evaluate the strength of the association using odds ratio (OR) with 95% confidence interval (CI). Overall, no significant association was found between the PARP-1 V762A polymorphism and cancer risk. In the stratified analyses, however, it was found that the variant A allele of the PARP-1 V762A polymorphism was associated with an increased risk of cancer among Asian populations (VA + AA vs. VV: OR = 1.11, 95% CI: 1.01-1.23; P(heterogeneity) = 0.210), but a decreased risk of cancer (VA + AA vs. VV: OR = 0.89, 95% CI: 0.80-1.00; P(heterogeneity) = 0.004) among Caucasian populations, especially for glioma risk (OR = 0.79, 95% CI: 0.69-0.90; P(heterogeneity) = 0.800). This meta-analysis found evidence for an association of the PARP-1 V 762A polymorphism with increased risk of cancer among Asians, but decreased risk of cancer among Caucasians, particularly of glioma. Further well-designed studies with large sample sizes of different ethnic populations and different cancer types are warranted to confirm these findings.
42 citations
Cites background from "Normal telomere length and chromoso..."
...It has been found that PARP-1 knockout mice (PARP-1 / ) treated with either alkylating agents or ã-irradiation displayed high genomic instability, high frequencies of chromosome aberrations, and shortened telomere compared with the wild-type mice [d’Adda di Fagagna et al., 1999; de Murcia et al., 1997; Samper et al., 2001]....
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...…knockout mice (PARP-1 / ) treated with either alkylating agents or ã-irradiation displayed high genomic instability, high frequencies of chromosome aberrations, and shortened telomere compared with the wild-type mice [d’Adda di Fagagna et al., 1999; de Murcia et al., 1997; Samper et al., 2001]....
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References
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TL;DR: P16 seems to act in a regulatory feedback circuit with CDK4, D-type cyclins and retinoblastoma protein, and inhibits the catalytic activity of theCDK4/cyclin D enzymes.
Abstract: The division cycle of eukaryotic cells is regulated by a family of protein kinases known as the cyclin-dependent kinases (CDKs). The sequential activation of individual members of this family and their consequent phosphorylation of critical substrates promotes orderly progression through the cell cycle. The complexes formed by CDK4 and the D-type cyclins have been strongly implicated in the control of cell proliferation during the G1 phase. CDK4 exists, in part, as a multi-protein complex with a D-type cyclin, proliferating cell nuclear antigen and a protein, p21 (refs 7-9). CDK4 associates separately with a protein of M(r) 16K, particularly in cells lacking a functional retinoblastoma protein. Here we report the isolation of a human p16 complementary DNA and demonstrate that p16 binds to CDK4 and inhibits the catalytic activity of the CDK4/cyclin D enzymes. p16 seems to act in a regulatory feedback circuit with CDK4, D-type cyclins and retinoblastoma protein.
3,716 citations
"Normal telomere length and chromoso..." refers methods in this paper
...As control for the two-hybrid assay we show interaction between the cell cycle proteins CDK4 and p16 as described previously (Table VI; Serrano et al., 1993)....
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TL;DR: The DNA of telomeres—the terminal DNA-protein complexes of chromosomes—differs notably from other DNA sequences in both structure and function, and has been shown to be essential for telomere maintenance and long-term viability.
Abstract: The DNA of telomeres--the terminal DNA-protein complexes of chromosomes--differs notably from other DNA sequences in both structure and function. Recent work has highlighted its remarkable mode of synthesis by the ribonucleoprotein reverse transcriptase, telomerase, as well as its ability to form unusual structures in vitro. Moreover, telomere synthesis by telomerase has been shown to be essential for telomere maintenance and long-term viability.
3,139 citations
TL;DR: Electron microscopy reported here demonstrated that TRF2 can remodel linear telomeric DNA into large duplex loops (t loops) in vitro, which may provide a general mechanism for the protection and replication of telomeres.
2,413 citations
TL;DR: Results indicate that telomerase is essential for telomere length maintenance but is not required for establishment of cell lines, oncogenic transformation, or tumor formation in mice.
2,066 citations
"Normal telomere length and chromoso..." refers background or methods in this paper
...These Robertsonian fusions are different from those found in late generation telomerase-deficient mice that have critically short telomeres (Blasco et al., 1997)....
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...5 embryos derived from heterozygous crosses as described (Blasco et al., 1997)....
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...Telomeres have an essential role in chromosome stability and are proposed to be biological determinants in the processes of tumorigenesis and aging (for reviews see Blackburn, 1991; Autexier and Greider, 1996; Greider, 1996; Blasco et al., 1997; Lee et al., 1998)....
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...Then the plugs were digested with MboI overnight and run in a pulse field gel electrophoresis as described (Blasco et al., 1997)....
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TL;DR: The history and present situation of Spanish language, culture, literature, cuisine, tourism, and more are explored in more detail in this booklet.
Abstract: TELOMERES DEFINED . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 579 TELOMERE FUNCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 580 SEQUENCE AND STRUCTURE OF TELOMERES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 581 SOLUTIONS FOR REPLICATION OF DNA TERMINI . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 586 STRUCTURE OF SUBTELOMERIC REGIONS.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 589 FORMA TION OF TELOMERES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ... . . . . . .. 591 PROTEINS THAT INTERACT WITH TELOMERES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 594 ARE TELOMERES REALLY ESSENTIAL? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 597 FUTURE PROSPECTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 598
1,923 citations
"Normal telomere length and chromoso..." refers background in this paper
...Vertebrate telomeres consist of tandem repeats of the sequence TTAGGG (for review see Blackburn, 1991)....
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...Telomeres have an essential role in chromosome stability and are proposed to be biological determinants in the processes of tumorigenesis and aging (for reviews see Blackburn, 1991; Autexier and Greider, 1996; Greider, 1996; Blasco et al., 1997; Lee et al., 1998)....
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