Shelterin complex and associated factors at human telomeres

Diotti, Raffaella; Loayza, Diego

doi:10.4161/nucl.2.2.15135

Cited by 147 publications

(120 citation statements)

References 159 publications

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“…These accessory factors, while found at telomeres, often possess functions unrelated to telomeres and their presence can be highly regulated or in lower quantities, than those observed for shelterin. 30 The functionality of these factors and their presence at telomeres play an important role for telomere integrity. Examples include ATM, ATR and Ku70/80.…”

Section: Resultsmentioning

confidence: 99%

TRIP6 and LPP, but not Zyxin, are present at a subset of telomeres in human cells

Sheppard

Savinova²,

Loayza³

2011

Cell Cycle

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T he protection of chromosome ends requires the inhibition of DNA damage responses at telomeres. This inhibition is exerted in great part by the shelterin complex, known to prevent inappropriate ATM and ATR activation. The molecular mechanisms by which shelterin protects telomeres are incompletely understood. Recently, we have implicated for the first time a class of molecules, LIM domain proteins, in telomere protection. This protection occurred through interaction with shelterin, possibly through POT1, and required the pair of LIM proteins TRIP6 and LPP, themselves part of the Zyxin family. The domain similarity between TRIP6, LPP and Zyxin led us to ask whether the latter also interacted with telomeres. Here, we show that there is specificity in the association of LIM proteins with telomeres: Zyxin, despite a high degree of similarity with TRIP6 and LPP, was not detected at telomeres, nor found in a complex with shelterin. TRIP6 and LPP, however, were detected by immunofluorescence at a small subset of telomeres, perhaps those that are critically short. We speculate that specific LIM proteins are part of complex events occurring in the context of the telomere dysfunction response and are possibly at play during the induction of senescence.

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Section: Resultsmentioning

confidence: 99%

TRIP6 and LPP, but not Zyxin, are present at a subset of telomeres in human cells

Sheppard

Savinova²,

Loayza³

2011

Cell Cycle

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“…Telomeres would be completely repaired by telomerase and related proteins in cancer cells contributes to the phenomenon (Hanahan et al, 2011;Mason et al, 2011), which are mediated by a stably associated complex-shelterin. Shelterin which is composed of six telomere proteins, including TRF1 (telomere repeat binding factor 1), TRF2 (telomere repeat binding factor 2), TIN2 (TRF1-interacting factor 2), TPP1 (POT1 and TIN2-interacting protein), Rap1 (telomeric repeat-binding factor 2-interacting protein 1) and POT1 (protection of telomeres) (de Lange, 2005;Diotti et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Expression of hPOT1 in HeLa Cells and the Probability of Gene Variation of hpot1 Exon14 in Endometrial Cancer are Much Higher than in Other Cancers

Liu

Pu²,

Huang³

et al. 2012

Asian Pacific Journal of Cancer Prevention

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To investigate the expression of hPOT1 in the HeLa cell line and screen point mutations of hpot1 in different tumor tissues a two step osmotic method was used to extract nuclear proteins. EMSA was performed to determine the expression of hPOT1 in the HeLa cell line. PCR was also employed to amplify the exon14 sequence of the hpot1 gene in various of cancer tissues. A SV gel and PCR clean-up system was performed to enrich PCR products. DNAStar was used to analyse the exon14 sequence of the hpot1 gene. hPOT1 was expressed in the HeLa cell line and the signal was gradually enhanced as the amount of extracted nuclear proteins increased. The DNA fragment of exon14 of hpot1 was successfully amplified in the HeLa cell line and all cancer tissues, point mutations being observed in 2 out of 3 cases of endometrial cancer (66.7%) despite the hpot1 sequence being highly conserved. However, the sequence of hpot1 exon14 do not demonstrate point mutations in most cancer tissues. Since hPOT1 was expressed in HeLa cell and the probability of gene point variants was obviously higher in endometrial cancer than other cancers, it may be involved in the pathogenesis of gynecological cancers, especially in cervix and endometrium.

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“…We report that BLM was required to repress the fragile phenotype specifically in telomeres formed by lagging strand DNA synthesis (lagging end telomeres) but had no role at leading end telomeres. TRF1 bound directly to BLM, and this interaction was required to mediate the replication of lagging end telomeres, establishing BLM as a shelterin accessory factor (for review, see Diotti and Loayza 2011). BLM was not required for the repression of ATR signaling by TRF1 and played no detectable role in preventing the association of sister telomeres.…”

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confidence: 99%

TRF1 negotiates TTAGGG repeat-associated replication problems by recruiting the BLM helicase and the TPP1/POT1 repressor of ATR signaling

et al. 2014

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The semiconservative replication of telomeres is facilitated by the shelterin component TRF1. Without TRF1, replication forks stall in the telomeric repeats, leading to ATR kinase signaling upon S-phase progression, fragile metaphase telomeres that resemble the common fragile sites (CFSs), and the association of sister telomeres. In contrast, TRF1 does not contribute significantly to the end protection functions of shelterin. We addressed the mechanism of TRF1 action using mouse conditional knockouts of BLM, TRF1, TPP1, and Rap1 in combination with expression of TRF1 and TIN2 mutants. The data establish that TRF1 binds BLM to facilitate lagging but not leading strand telomeric DNA synthesis. As the template for lagging strand telomeric DNA synthesis is the TTAGGG repeat strand, TRF1-bound BLM is likely required to remove secondary structures formed by these sequences. In addition, the data establish that TRF1 deploys TIN2 and the TPP1/POT1 heterodimers in shelterin to prevent ATR during telomere replication and repress the accompanying sister telomere associations. Thus, TRF1 uses two distinct mechanisms to promote replication of telomeric DNA and circumvent the consequences of replication stress. These data are relevant to the expression of CFSs and provide insights into TIN2, which is compromised in dyskeratosis congenita (DC) and related disorders.

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Shelterin complex and associated factors at human telomeres

Cited by 147 publications

References 159 publications

TRIP6 and LPP, but not Zyxin, are present at a subset of telomeres in human cells

TRIP6 and LPP, but not Zyxin, are present at a subset of telomeres in human cells

Expression of hPOT1 in HeLa Cells and the Probability of Gene Variation of hpot1 Exon14 in Endometrial Cancer are Much Higher than in Other Cancers

TRF1 negotiates TTAGGG repeat-associated replication problems by recruiting the BLM helicase and the TPP1/POT1 repressor of ATR signaling

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