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Journal ArticleDOI

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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Citations
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Journal ArticleDOI
TL;DR: It is observed that the Rad9/Hus1/Rad1 (911) complex, previously known for its functions in DNA metabolism and DNA damage responses, is constitutively associated with telomeres and plays an important role in their maintenance.
Abstract: "Natura non facit saltum" (nature makes no leap) the Latins used to say, meaning that nature does not like discontinuities. Cells make no exception and indeed any discontinuity in the DNA double helix is promptly detected, triggering an alteration of cell proliferation and an attempt to repair. Yet, linear chromosomes bear DNA ends that are compatible with normal cell proliferation and they escape, under normal conditions, any repair. How telomeres, the chromosomes tips, achieve that is not fully understood. We recently observed that the Rad9/Hus1/Rad1 (911) complex, previously known for its functions in DNA metabolism and DNA damage responses, is constitutively associated with telomeres and plays an important role in their maintenance. Here, we summarize the available data and discuss the potential mechanisms of 911 action at telomeres.

13 citations


Cites background from "Normal telomere length and chromoso..."

  • ...Despite a tight inhibitory control of DDR at telomeres, mammalian chromosome ends are nevertheless a physiological substrate of the DDR apparatus as the inactivation of genes encoding certain DDR factors involved in DSB repair such as DNA-PK [26-30], Parp-1 [31,32], Rad51D [33] and Wrn [34], as well as components of the AtmMrell/Rad50/Nbsl pathway [35-38] results in telomere dysfunction....

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  • ...Despite a tight inhibitory control of DDR at telomeres, mammalian chromosome ends are nevertheless a physiological substrate of the DDR apparatus as the inactivation of genes encoding certain DDR factors involved in DSB repair such as DNA-PK [26-30], Parp-1 [31,32], Rad51D [33] and Wrn [34], as well as components of the AtmMrell/Rad50/Nbsl pathway [35-38] results in telomere dysfunction....

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Journal ArticleDOI
TL;DR: A review of methods for the detection of telomerase in cancer, including RNA in situ hybridization and immunohistochemistry, which can be performed to examine expression levels and localization of the catalytic subunit of the enzyme.
Abstract: A number of methods exist to detect levels of telomerase activity and the presence of telomerase subunits in a variety of tissues. As telomerase activation seems to be an important step in tumorigenesis, accurate detection of the presence and activity of the enzyme and its subunits is vital. The original method of detecting telomerase activity was developed by Kim and coworkers in 1994, and was termed the telomeric repeat amplification protocol. This assay led to a staggering increase in the number of telomerase-associated publications in scientific journals (85 publications from 1974–1994, 5063 publications from 1994–2004). A number of methods have been described to detect telomeres and to measure their length, with the standard measurement of telomere length performed using a modification of the Southern blot protocol. RNA in situ hybridization can be performed to detect levels of the RNA component of telomerase, and standard in situ hybridization and immunohistochemistry can be applied to examine expre...

12 citations

Journal ArticleDOI
30 Jan 2013-PLOS ONE
TL;DR: Data support a direct link between CSA exposure and MN formation measured in adults that is not attributable to genetic or environmental factors shared by siblings and indicates that the biological effects of CSA on MN formation may be cumulative.
Abstract: Background Childhood sexual abuse (CSA) is a traumatic life event associated with an increased lifetime risk for psychopathology/morbidity The long-term biological consequences of CSA-elicited stress on chromosomal stability in adults are unknown The primary aim of this study was to determine if the rate of acquired chromosomal changes, measured using the cytokinesis-block micronucleus assay on stimulated peripheral blood lymphocytes, differs in adult female monozygotic twins discordant for CSA

11 citations


Cites background from "Normal telomere length and chromoso..."

  • ...Given that both telomere shortening and/or inflammationrelated generation of oxygen and/or nitrogen species are phenomena that have been associated with an increased frequency of acquired chromosomal abnormalities [13,14,15,16,17,18,19], we hypothesize that an alternative or additional biological effect of stress could be the acquisition of somatic cell chromosomal instability....

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BookDOI
01 Jan 2015
TL;DR: This book, written by leading investigators, brings together the latest knowledge about key aspects of the most rapidly progressing fields of tumor escape and tumor resistance to CTL to help overcome the inherent limitations of current treatments.
Abstract: This book, written by leading investigators, brings together the latest knowledge about key aspects of the most rapidly progressing fields of tumor escape and tumor resistance to CTL. Readers will benefit from a collection of outstanding surveys that cover some factors regulating resistance to CTL cytotoxicity, the influence of tumor microenvironment, and the resistance to death ligands, mediated apoptosis, and means to reverse resistance. This remarkable volume also emphasizes the future directions that may lead to the design of more innovative, refined, and integrative immunotherapies to target tumor plasticity and heterogeneity, and help to overcome the inherent limitations of current treatments. By providing a broad scope of innovative concepts in the burgeoning field of cancer biology and immunotherapy, this volume will be of exceptional interest and a valuable reference for scientists, clinicians, health professionals, and biopharmaceutical companies working in the field of cancer immunotherapy.

8 citations

Journal Article
01 Jan 1999-Cells
TL;DR: The yeast Sir2/3/4p complex is found in abundance at telomeres, where it participates in the formation of silent heterochromatin and telomere maintenance as mentioned in this paper.
Abstract: The yeast Sir2/3/4p complex is found in abundance at telomeres, where it participates in the formation of silent heterochromatin and telomere maintenance. Here, we show that Sir3p is released from telomeres in response to DNA double-strand breaks (DSBs), binds to DSBs, and mediates their repair, independent of cell mating type. Sir3p relocalization is S phase specific and, importantly, requires the DNA damage checkpoint genes MEC1 and RAD9. MEC1 is a homolog of ATM, mutations in which cause ataxia telangiectasia (A-T), a disease characterized by various neurologic and immunologic abnormalities, a predisposition for cancer, and a cellular defect in repair of DSBs. This novel mode by which preformed DNA repair machinery is mobilized by DNA damage sensors may have implications for human diseases resulting from defective DSB repair.

8 citations

References
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Journal ArticleDOI
16 Dec 1993-Nature
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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Journal ArticleDOI
18 Apr 1991-Nature
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

Journal ArticleDOI
14 May 1999-Cell
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

Journal ArticleDOI
03 Oct 1997-Cell
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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Journal ArticleDOI
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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