Telomere-driven replicative senescence is a stress response

Zglinicki, Thomas von; Petrie, Joanne; Kirkwood, Tbl

doi:10.1038/nbt0303-229b

Cited by 70 publications

(38 citation statements)

References 7 publications

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“…Telomere length is a thoroughly controlled feature and a potent regulator in cell biology. 30,31 Therefore, telomeres represent more than a mere cell division counter due to the end-replication problem. We found a significantly higher rate of telomere shortening during low dose hydrogen peroxide treatment.…”

Section: Discussionmentioning

confidence: 99%

Oxidative stress induces senescence in chondrocytes

Brandl¹,

Hartmann²,

Bechmann³

et al. 2011

Journal Orthopaedic Research

116

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Cellular senescence is a program activated during diverse situations of cell stress. Chondrocytes differ from other somatic cells as articular cartilage is an avascular tissue. The effects of oxidative stress on chondrocytes are still unknown. Our studies were to investigate into the proliferation potential, cytological features and the telomere linked stress response system of human osteoarthritic chondrocytes, subjected to acute or prolonged oxidant challenge with hydrogen peroxide. Telomere length was measured using the telomere restriction fragment assay, gene expression was determined by RT-PCR. Sub-lethal doses of oxidative stress induced cell-cycle arrest, senescentmorphological features and senescence-associated b-galactosidase positivity. Prolonged oxidative treatment had no effects on cell proliferation or morphology. Sub-lethal and prolonged low doses of oxidative stress considerably accelerated telomere attrition. The effects of sublethal oxidative stress regarding proliferation and telomere biology were more distinct in senescent cells. Acute oxidant insult caused upregulation of p21 expression to levels comparable to senescent cells. TRF2 protects telomere ends and showed elevated expression levels. SIRT1 and XRCC5 enable cells to cope with unfavorable growing conditions. Both were up-regulated after oxidant insult, but expression levels decreased in aging cells. Taken Keywords: cellular senescence; oxidative stress; telomeres; DNA damage; human chondrocytes Cellular aging or senescence refers to metabolically active somatic cells having entered a state of permanent growth arrest. Replicative senescence has been associated with telomere shortening. Telomeres consist of noncoding repetitive DNA sequences and associated proteins located at the end of linear chromosomes. Human telomeres form a 2,000-30,000 base pair (bp) array of duplex DNA strand of TTAGGG repeats, ending in a 100-200 bp nucleotide 3 0 single strand overhang invading the duplex array to form a lariat-like loop structure (t-loop). Telomeric repeats ensure the complete replication of encoding DNA. Chromosome ends, uncapped by telomeres, are susceptive to degradation and fusion and can activate DNA damage checkpoints. 1 A six-protein complex-known as telosome or shelterin complex-functions to form and maintain the t-loop structure. TRF1 and TRF2 are part of the core telomeric proteins. Various signaling pathways coordinating telomere function and cell cycle regulation start off the telosome complex. TRF1 modulates the length of telomeres. TRF2 is important for stabilizing the t-loop structure. 2,3 XRCC5 and SIRT1 are associated with the telomerenucleo-protein complex and link telomere biology and DNA damage checkpoints with genes involved in other cellular stress responses. XRCC5 is involved in repairing DNA double-strand breaks. 4,5 SIRT1 is a negative regulator of p53 and prevents growth arrest, senescence, and apoptosis. 6 Telomere uncapping, DNA damage foci at telomeres 7 and oxidative insults cause p21 elevation. The p21...

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Section: Discussionmentioning

confidence: 99%

Oxidative stress induces senescence in chondrocytes

Brandl¹,

Hartmann²,

Bechmann³

et al. 2011

Journal Orthopaedic Research

116

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“…There is a consensus from various studies indicating oxidative stress as a cause of telomere shortening (38)(39)(40). It is less clear The cells were then fixed and immunostained for Ape1 (green) and POT1 (red).…”

Section: Discussionmentioning

confidence: 99%

Essential role for mammalian apurinic/apyrimidinic (AP) endonuclease Ape1/Ref-1 in telomere maintenance

Madlener¹,

Ströbel

Vose

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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The major mammalian apurinic/apyrimidinic endonuclease Ape1 is a multifunctional protein operating in protection of cells from oxidative stress via its DNA repair, redox, and transcription regulatory activities. The importance of Ape1 has been marked by previous work demonstrating its requirement for viability in mammalian cells. However, beyond a requirement for Ape1-dependent DNA repair activity, deeper molecular mechanisms of the fundamental role of Ape1 in cell survival have not been defined. Here, we report that Ape1 is an essential factor stabilizing telomeric DNA, and its deficiency is associated with telomere dysfunction and segregation defects in immortalized cells maintaining telomeres by either the alternative lengthening of telomeres pathway (U2OS) or telomerase expression (BJ-hTERT), or in normal human fibroblasts (IMR90). Through the expression of Ape1 derivatives with sitespecific changes, we found that the DNA repair and N-terminal acetylation domains are required for the Ape1 function at telomeres. Ape1 associates with telomere proteins in U2OS cells, and Ape1 depletion causes dissociation of TRF2 protein from telomeres. Consistent with this effect, we also observed that Ape1 depletion caused telomere shortening in both BJ-hTERT and in HeLa cells. Thus, our study describes a unique and unpredicted role for Ape1 in telomere protection, providing a direct link between base excision DNA repair activities and telomere metabolism.genome stability | chromosome stability | endogenous DNA damage H uman cells must cope with a substantial number of spontaneous apurinic/apyrimidinic (AP) sites (1, 2). Noninstructional AP sites are mutagenic, and they can inhibit replication and transcription (3, 4). The human AP endonuclease Ape1, also called Ref-1, referring to a redox regulatory activity, is a crucial enzyme for the recognition and processing of AP sites in the base excision repair (BER) of DNA (5, 6). Ape1 has also been reported to possess a redox regulatory function (7,8), and it is thought to function as a transacting factor in gene regulation (9-12). Recently, a novel role for Ape1 in RNA quality control has also been suggested (13,14).Mouse embryos deleted for the APEX1 gene (encoding Ape1) die during embryogenesis (15-17). The accumulated evidence points to a vital role of Ape1 in the cell, but it has been challenging to explore the underlying molecular mechanisms. Attempts to dissect the essential domain(s) of Ape1 for cell survival have indicated the importance of both its DNA repair activity and two N-terminal lysine residues implicated in acetylation-mediated gene regulation, but not the Ref-1 redox activity (18,19).In this study, we report another function for Ape1: the protection of telomeres. Loss of Ape1 interferes with the association of telomeric repeat-binding factor (TRF)2 protein with telomeres, and the resulting telomere uncapping gives rise to genomic instability. The AP endonuclease and gene regulatory domains of Ape1 are essential for stabilization of telomeric DNA. Thus, this unpr...

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“…Thus, telomere shortening has been suggested to be a 'molecular clock' of the aging process. Recently, Zglinicki et al reported an increase of the rate of telomere shortening by oxidative stress in human fibroblasts (3,4). However, the mechanism for the increase in telomere shortening rate by oxidative stress remains to be clarified.…”

Section: The Role Of Reactive Oxygen Species In Agingmentioning

confidence: 99%

“…Furthermore, UVA irradiation dose-dependently increased the formation of 8-oxodG in WI-38 fibroblasts. In order to clarify the mechanism of the acceleration of telomere shortening, we investigated site-specific DNA damage induced by UVA irradiation in the presence of endogenous photosensitizers using 32 P-5'-end labeled DNA fragments containing telomeric oligonucleotide (TTAGGG) 4 . UVA irradiation with riboflavin induced Fig.…”

Section: The Role Of Reactive Oxygen Species In Agingmentioning

confidence: 99%

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Sequence-specific DNA damage by reactive oxygen species: Implications for carcinogenesis and aging

Oikawa

2005

Environ Health Prev Med

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Reactive oxygen species (ROS) generated by environmental chemicals can cause sequence-specific DNA damage, which may lead to carcinogenesis and aging. We investigated the mechanism of DNA damage by environmental chemicals (catechol, propyl gallate and bisphenol-A), homocysteine and UVA radiation using human cultured cell lines and 32 P-labeled DNA fragments. Carcinogenic catechol induced piperidine-labile sites frequently at thymine residues in the presence of Cu(II) and NADH. Furthermore, catechol increased the formation of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG), a characteristic oxidative DNA lesion, in human leukemia cell line HL-60, but not in HP100, a hydrogen peroxide (H 2 O 2 )-resistant cell line derived from HL-60. Thus, it is concluded that oxidative DNA damage through generation of H 2 O 2 plays an important role in the carcinogenic process of catechol. In addition, an environmental factor, bisphenol-A, and a dietary factor, propyl gallate, also induced sequence-specific DNA damage via ROS generation.UVA, as well as UVB, contributes to photoaging. In humans, telomere shortening is believed to be associated with cell senescence. In this study, we investigated the shortening rate of telomeres in human WI-38 fibroblasts exposed to UVA irradiation. The telomere length (as measured by terminal restriction fragment length) in WI-38 fibroblasts irradiated with UVA decreased with increasing the irradiation dose. UVA irradiation with riboflavin caused damage specifically at the GGG sequence in the DNA fragments containing telomere sequence (TTAGGG) 4 . We concluded that the GGG-specific damage in telomere sequence induced by UVA irradiation participates in the increase of the telomere shortening rate.In this report, we show our experimental results and discuss the mechanisms of sequence-specific DNA damage in relation to carcinogenesis and aging.

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Telomere-driven replicative senescence is a stress response

Cited by 70 publications

References 7 publications

Oxidative stress induces senescence in chondrocytes

Oxidative stress induces senescence in chondrocytes

Essential role for mammalian apurinic/apyrimidinic (AP) endonuclease Ape1/Ref-1 in telomere maintenance

Sequence-specific DNA damage by reactive oxygen species: Implications for carcinogenesis and aging

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