Actions of human telomerase beyond telomeres

Cong, Yu‐Sheng; Shay, Jerry W.

doi:10.1038/cr.2008.74

Cited by 206 publications

(169 citation statements)

References 77 publications

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“…These studies are not inconsistent with the idea that telomerase has functions beyond telomere stabilization. There is evidence for a diverse range of noncanonical telomerase functions in proliferation, stem cells, apoptosis, and gene expression (51). For example, Masutomi et al reported that hTERT participates in chromatin maintenance and that hTERT affects the response to DNA double-strand breaks.…”

Section: Discussionmentioning

confidence: 99%

Progerin-Induced Replication Stress Facilitates Premature Senescence in Hutchinson-Gilford Progeria Syndrome

Wheaton

Campuzano

et al. 2017

Molecular and Cellular Biology

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Hutchinson-Gilford progeria syndrome (HGPS) is caused by a mutation in LMNA that produces an aberrant lamin A protein, progerin. The accumulation of progerin in HGPS cells leads to an aberrant nuclear morphology, genetic instability, and p53-dependent premature senescence. How p53 is activated in response to progerin production is unknown. Here we show that young cycling HGPS fibroblasts exhibit chronic DNA damage, primarily in S phase, as well as delayed replication fork progression. We demonstrate that progerin binds to PCNA, altering its distribution away from replicating DNA in HGPS cells, leading to ␥H2AX formation, ATR activation, and RPA Ser33 phosphorylation. Unlike normal human cells that can be immortalized by enforced expression of telomerase alone, immortalization of HGPS cells requires telomerase expression and p53 repression. In addition, we show that the DNA damage response in HGPS cells does not originate from eroded telomeres. Together, these results establish that progerin interferes with the coordination of essential DNA replication factors, causing replication stress, and is the primary signal for p53 activation leading to premature senescence in HGPS. Furthermore, this damage response is shown to be independent of progerin farnesylation, implying that unprocessed lamin A alone causes replication stress.KEYWORDS HGPS, progerin, senescence, aging, p53, telomere T he study of children with rare accelerated aging (progeria) syndromes has provided insight into the normal process of aging. Hutchinson-Gilford progeria syndrome (HGPS) is caused by a heterozygous, autosomal dominant mutation in LMNA (1), the gene that encodes lamin A, a key structural protein in the nuclear lamina. The lamina, a protein network that lines the inner nuclear membrane, provides structural support for the nucleus and is important for chromatin attachment, DNA replication, nuclear organization, and gene transcription in ways that are not completely understood. Farnesylation of prelamin A at the C terminus allows targeting to the inner nuclear membrane, where it is subsequently cleaved by the zinc metalloproteinase Zmpste24 to release mature lamin A into the lamina and nucleoplasm. In HGPS, the most common LMNA mutation (G608G) activates a cryptic splice donor site in exon 11, resulting in prelamin A mRNA with a 150-bp internal deletion, leading to a 50-amino-acid truncation in a region that contains the Zmpste24 cleavage site (reviewed in reference 2). The mutant lamin, termed progerin, retains the farnesyl lipid anchor, interferes with the integrity of the nuclear lamina, and causes the formation of misshapen nuclei. The retention of progerin on the inner nuclear membrane interferes with the function and normal distribution of lamin A, causing a loss of peripheral heterochromatin, increased DNA damage, impaired recruitment of DNA repair proteins to sites of DNA damage (3), and persistent activation of DNA damage response proteins (4). In addition to its

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Section: Discussionmentioning

confidence: 99%

Progerin-Induced Replication Stress Facilitates Premature Senescence in Hutchinson-Gilford Progeria Syndrome

Wheaton

Campuzano

et al. 2017

Molecular and Cellular Biology

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“…[33][34][35] We next examined the regulation of mTert expression in primary cultured inner medullary collecting duct (IMCD) cells, because most immortalized cell lines overexpress telomerase and would therefore be unsuitable to examine its regulation. 36 IMCD cells expressed high levels of mTert mRNA at baseline, compared with renal cortex and papilla ( Figure 7A).…”

Section: Mtert Is Induced By Osmotic Shockmentioning

confidence: 99%

Characterization and Fate of Telomerase-expressing Epithelia during Kidney Repair

Song

Czerniak

Wang

et al. 2011

Journal of the American Society of Nephrology

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After acute kidney injury, mice with short telomeres develop increased damage with reduced proliferative capacity, which suggests an important role for telomere length in kidney repair. The enzyme telomerase reverse transcriptase (mTert) regulates telomere length; embryonic stem cells and certain adult stem cells express mTert, but whether cells in the adult kidney express mTert and whether these cells play a role in renal repair are unknown. Here, we found that telomerase protein and mRNA were highly enriched in renal papilla, a proposed niche of kidney stem cells. Using mTert-GFP reporter mice, we detected mTert in a subset of papillary epithelial cells comprising the collecting duct predominantly but also the loop of Henle. Approximately 5% of mTert-GFP ϩ cells were label retaining, a characteristic of stem cells. mTert mRNA levels increased in renal papilla after ischemia-reperfusion injury, but genetically labeled mTert-expressing papillary cells neither divided nor migrated out of the renal papilla during kidney repair. In summary, these data suggest that cells expressing telomerase reverse transcriptase are not a progenitor-cell population, and they do not play a direct role in kidney repair.

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“…In addition, hTERT has been implicated in promotion of cell survival and proliferation (Cao et al, 2002). Thus, regulatory pathways of hTERT in transcriptional and posttranslational levels have been considered as a critical factor in tumorigenesis and aging (Urquidi et al, 2000;Cong and Shay, 2008). For example, the transcriptional expression of hTERT is suppressed by p53 and Mad1, whereas Myc and Sp1, Bmi-1, E6 protein and insulin-like growth factor 1 function as positive transcriptional activators Veldman et al, 2001;Akiyama et al, 2002;Dimri et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

Hdm2 negatively regulates telomerase activity by functioning as an E3 ligase of hTERT

Lee

et al. 2010

Oncogene

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In this study, we identified posttranslational regulation of human telomerase reverse-transcriptase (hTERT) by the E3 ligase Hdm2. The telomerase activity generated by exogenous hTERT in U2OS cells was reduced on adriamycin treatment. The overexpressed levels of hTERT were also decreased under the same conditions. These processes were reversed by treatment with a proteasome inhibitor or depletion of Hdm2. Furthermore, intrinsic telomerase activity was increased in HCT116 cells with ablation of Hdm2. Immunoprecipitation analyses showed that hTERT and Hdm2 bound to each other in multiple domains. Ubiquitination analyses showed that Hdm2 could polyubiquitinate hTERT principally at the N-terminus, which was further degraded in a proteasomedependent manner. An hTERT mutant with all five lysine residues at the N-terminus of hTERT that mutated to arginine became resistant to Hdm2-mediated ubiquitination and degradation. In U2OS cells, depletion of Hdm2 or addition of the Hdm2-resistant hTERT mutant strengthened the cellular protective effects against apoptosis. Similar results were obtained with the Hdm2-stable H1299 cell line. These observations indicate that Hdm2 is an E3 ligase of hTERT.

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Actions of human telomerase beyond telomeres

Cited by 206 publications

References 77 publications

Progerin-Induced Replication Stress Facilitates Premature Senescence in Hutchinson-Gilford Progeria Syndrome

Progerin-Induced Replication Stress Facilitates Premature Senescence in Hutchinson-Gilford Progeria Syndrome

Characterization and Fate of Telomerase-expressing Epithelia during Kidney Repair

Hdm2 negatively regulates telomerase activity by functioning as an E3 ligase of hTERT

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