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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE193523 | GEO | 2022/11/04

REPOSITORIES: GEO

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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

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

Genome-wide maps of RAP1 binding sites.

Project description:By performing chromatin immunoprecipitation coupled with ultra-high-throughput sequencing (ChIP-seq), we find that RAP1 binds to telomeres as well as to extra-telomeric sites through the (TTAGGG)2 consensus motif. Extra-telomeric RAP1 binding sites are particularly abundant at subtelomeric regions, and this is in agreement with preferential deregulation of subtelomeric genes in Rap1-deficient cells. Significantly, more than 70% of extratelomeric RAP1 binding sites are located in the vicinity of known genes and about 40% of the genes deregulated in Rap1-null cells contain binding sites for RAP1, suggesting a role of RAP1 in transcriptional control. Examination of RAP1 binding by CHIP-seq in two independent wild-type mefs using as negative control two independent RAP1-deleted mefs

2010-07-10 | E-GEOD-20867 | biostudies-arrayexpress

ZBTB10 binds the telomeric variant repeat TTGGGG and interacts with TRF2

Project description:Telomeres are the ends of linear chromosomes and together with the shelterin complex present an essential feature for genome integrity. Vertebrate telomeres usually consist of hexameric TTAGGG repeats, however, in cells that use the alternative lengthening of telomeres (ALT) mechanism, variant repeat sequences are interspersed throughout telomeres. Previously, it was shown that NR2C/F transcription factors bind to TCAGGG variant repeats and contribute to telomere maintenance in ALT cells. While specific binders to other variant repeat sequences have been lacking to date, we here identify ZBTB10 as the first TTGGGG-binding protein and demonstrate direct binding via the two zinc fingers with affinity in the nanomolar range. Concomitantly, ZBTB10 co-localizes with a subset of telomeres in ALT-positive U2OS cells and interacts with TRF2/RAP1 via the N-terminal region of TRF2. Our data establishes ZBTB10 as a novel variant repeat-specific binding protein at ALT telomeres.

2018-12-17 | PXD010672 | Pride

Genome-wide maps of RAP1 binding sites.

2010-07-10 | GSE20867 | GEO

Mutational analysis of Rap1 reveals specific vulnerability for long telomeres fusions

Project description:The conserved Rap1 protein is part of the shelterin complex that plays critical roles in chromosome end protection and telomere length homeostasis. Previous studies addressed how fission yeast Rap1 contributes to telomere length maintenance, but the mechanism by which the protein inhibits end fusions has remained elusive. Here, we use a genetic screen in combination with high throughput sequencing to identify several amino acid positions in Rap1 that have a key role in end protection. Interestingly, mutations at these sites render cells susceptible to genome instability in a conditional manner with longer telomeres being prone to undergoing end fusions, while short telomeres are sufficiently protected. The protection of long telomeres requires their nuclear envelope attachment mediated by the Rap1-Bqt4 interaction. Our data demonstrates that longer telomeres pose an additional challenge for the maintenance of genome integrity and provides an explanation for a species-specific upper limit in telomere length.

2022-08-10 | GSE190759 | 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

RAP1 protects from obesity, diabetes and metabolic syndrome through its extra telomeric role regulating gene expression (old mouse liver)

Project description:RAP1 is one of the components of shelterin, the capping complex at chromosome ends or telomeres. Unlike other shelterins, however, RAP1 is not essential for preventing telomere fusions. RAP1 also binds along chromosome arms, where it is proposed to regulate gene expression. To investigate the non-telomeric roles of RAP1 in vivo, we generated a RAP1 whole-body knock-out mouse model. Unexpectedly, these mice presented an early onset of obesity, which was particularly severe in females and was aggravated under a high-fat diet. Rap1-deficient mice showed abnormal accumulation of fat in abdominal depots and developed signs of type II diabetes and metabolic syndrome, including hepatic steatosis and high fasting plasma levels of insulin, glucose, cholesterol, and alanine transaminase. Gene expression analyses of the liver and visceral white fat from Rap1-deficient mice before the onset of obesity indicated deregulation of key metabolic transcriptional programs including fatty acid metabolism, PPARa signalling and glucose metabolism. Transcriptome and Western blotting analyses in liver further identified Ppara and Pgc1a and their target genes as the key metabolic pathways affected by Rap1 deletion. Finally, we show here that RAP1 binds to Ppara and Pgc1a loci and modulates their transcription. These findings underscore an unprecedented role for a telomere-binding protein in the regulation of metabolism. 2 condition experiment: WT versus Rap1 knockout. Tissue: liver. 3 biological replicates per genotype. Mice were 30 weeks old.

2013-06-21 | E-GEOD-43173 | biostudies-arrayexpress

RAP1 protects from obesity, diabetes and metabolic syndrome through its extra telomeric role regulating gene expression (young mouse liver)

Project description:RAP1 is one of the components of shelterin, the capping complex at chromosome ends or telomeres. Unlike other shelterins, however, RAP1 is not essential for preventing telomere fusions. RAP1 also binds along chromosome arms, where it is proposed to regulate gene expression. To investigate the non-telomeric roles of RAP1 in vivo, we generated a RAP1 whole-body knock-out mouse model. Unexpectedly, these mice presented an early onset of obesity, which was particularly severe in females and was aggravated under a high-fat diet. Rap1-deficient mice showed abnormal accumulation of fat in abdominal depots and developed signs of type II diabetes and metabolic syndrome, including hepatic steatosis and high fasting plasma levels of insulin, glucose, cholesterol, and alanine transaminase. Gene expression analyses of the liver and visceral white fat from Rap1-deficient mice before the onset of obesity indicated deregulation of key metabolic transcriptional programs including fatty acid metabolism, PPARa signalling and glucose metabolism. Transcriptome and Western blotting analyses in liver further identified Ppara and Pgc1a and their target genes as the key metabolic pathways affected by Rap1 deletion. Finally, we show here that RAP1 binds to Ppara and Pgc1a loci and modulates their transcription. These findings underscore an unprecedented role for a telomere-binding protein in the regulation of metabolism. 2 condition experiment: WT versus Rap1 knockout. Tissue: liver. 4 biological replicates per genotype. Mice were 10 weeks old.

2013-06-21 | E-GEOD-43171 | biostudies-arrayexpress