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Aberrant expression and localization of the RAP1 shelterin protein contributes to age-related phenotypes

ABSTRACT: Aberrant expression and localization of the RAP1 shelterin protein contributes to age-related phenotypes

PROVIDER: PRJNA796533 | ENA |

REPOSITORIES: ENA

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Aberrant expression and localization of the RAP1 shelterin protein contributes to age-related phenotypes [2019]

Project description:Aberrant expression and localization of the RAP1 shelterin protein contributes to age-related phenotypes [2019]

| PRJNA796537 | ENA

Aberrant expression and localization of the RAP1 shelterin protein contributes to age-related phenotypes [2017]

Project description:Aberrant expression and localization of the RAP1 shelterin protein contributes to age-related phenotypes [2017]

| PRJNA796527 | ENA

Aberrant expression and localization of the RAP1 shelterin protein contributes to age-related phenotypes [2017]

Project description:Short telomeres induce a DNA damage response (DDR) that evokes apoptosis or senescence in human cells. An extant question is the contribution of this DDR to the phenotypes observed in telomeropathies. One exemplar is RAP1, a telomere-associated protein that also controls transcription at extratelomeric regions. To distinguish these roles, we generated a knock-in mouse containing a Rap1 variant unable to bind telomeres but which did not result in eroded telomeres or a DDR. Rap1 variant MEFs exhibited decreased RAP1 expression and re-localization away from telomeres, with an increased cytosolic distribution akin to that observed in aging human fibroblasts. Rap1 knock-in mice were viable, but exhibited transcriptional alterations, proinflammatory cytokine/chemokine signaling, decreased lifespans, increased body weight/fasting blood glucose levels, increased spontaneous tumor incidence, and behavioral deficits. Taken together, our data indicate that some of the underlying mechanisms that drive telomeropathies may arise from phenotypes distinct from a telomere-induced DDR.

2022-11-04 | GSE193520 | GEO

Aberrant expression and localization of the RAP1 shelterin protein contributes to age-related phenotypes [2019]

2022-11-04 | GSE193523 | GEO

Aberrant expression and localization of the RAP1 shelterin protein contributes to age-related phenotypes

Project description:This SuperSeries is composed of the SubSeries listed below.

2022-11-04 | GSE193524 | GEO

Aberrant expression and localization of the RAP1 shelterin protein contribute to age-related phenotypes.

Project description: Not available

| S-EPMC9704629 | biostudies-literature

A genetic interaction between RAP1 and telomerase reveals an unanticipated role for RAP1 in telomere protection

Project description:RAP1 is one of the components of mammalian shelterin, the capping complex at chromosome ends or telomeres, although its role in telomere protection has remained elusive. RAP1 binds along chromosome arms, where it regulates gene expression and has been shown to function in metabolism control. Telomerase is the enzyme that elongates telomeres and its deficiency causes a premature aging in mice. We describe an unanticipated genetic interaction between RAP1 and telomerase. While RAP1 deficiency alone does not impact in mouse survival, mice lacking both RAP1 and telomerase show a progressive decreased survival with increasing mouse generation as compared to telomerase single mutants. Telomere shortening was more pronounced in Rap1-/- Terc-/- than in Terc-/- counterparts, leading to an earlier onset of DNA damage and its consequent DNA damage response as well as accelerated degenerative pathologies in the intestines. In its turn, telomerase deficiency abolishes RAP1-mediated obesity and liver pathologies. Mouse embryonic fibroblasts with shorten telomeres present less amount of telomere-bound RAP1 but in contrast show higher numbers of RAP1 bound extratelomeric sites genomewide. Absence of RAP1 leads to deregulation of several metabolic pathways, and these changes were more pronounce in cells with short telomeres suggesting that RAP1 release from telomere foci could constitute a coordinated genomic response to telomere shortening. Our findings also demonstrate that although RAP1 is not a key factor in telomere capping under normal conditios, under stress situation such as critical telomere shortening RAP1 exerts an important function for telomere protection and justify its evolutionary conservation as a shelterin component in mammalian cells.

2016-11-16 | GSE79996 | GEO

ZNF524 directly binds telomeres and supports their integrity via TRF2/RAP1

Project description:Telomeres are nucleoprotein structures at the ends of linear chromosomes. In humans, they consist of TTAGGG repeats, which are bound by dedicated proteins such as the shelterin complex. This complex consists of six proteins (TRF1, TRF2, RAP1, POT1, TPP1 and TIN2) and blocks unwanted DNA damage repair at telomeres, e.g. by suppressing non-homologous end joining (NHEJ) through its subunit TRF2. While shelterin does not work autonomously, additional direct telomere binding proteins have been described to function in a supplementary role. We here describe ZNF524, a zinc finger protein that directly binds to telomeric repeats with nanomolar affinity and reveal the base-specific sequence recognition by co-crystallization with telomeric DNA. ZNF524 localizes to telomeres and specifically maintains the presence of the TRF2/RAP1 subcomplex at telomeres without affecting the other shelterin members. Loss of ZNF524 concomitantly results in an increase in DNA damage signaling and recombination events. Overall, we identified ZNF524 as a direct telomere binding protein and propose that ZNF524 is involved in the maintenance of telomere integrity by promoting TRF2/RAP1 subcomplex binding.

2023-10-21 | PXD024630 | Pride

ZNF524 directly binds telomeres and supports their integrity via TRF2/RAP1

2023-10-22 | PXD031416 | Pride

TALEN gene knockouts reveal no requirement for the shelterin protein Rap1 in telomere protection and length regulation

Project description:Gene expression of human knockouts of telomere-protein Rap1 were compared to their wildtype counterparts in mutliple cell lines (available from the ATCC repository). We discovered that Rap1, desite being mostly associated with the telomere, performed a conserved role in transcriptional regulation, as evidenced by a number of genes that were differentially regulated upon deletion of Rap1.

2014-09-30 | GSE61900 | GEO

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