Mammalian Telomeres Resemble Fragile Sites and Require TRF1 for Efficient Replication

Sfeir, Agnel; Kosiyatrakul, Settapong T.; Hockemeyer, Dirk; MacRae, Sheila L.; Karlseder, Jan; Schildkraut, Carl L.; Lange, Titia de

doi:10.1016/j.cell.2009.06.021

Cited by 870 publications

(1,106 citation statements)

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“…The analysis of metaphase spreads showed that Ft1 kof/kof MEFs exhibit multiple telomeric signals (MTS, also known as fragile telomeres) and sister telomere associations (STA) (Figure 2g–i and Figure S1e). These types of telomere aberrations are considered hallmarks of defective telomere replication (Sfeir et al., 2009). Ft1 kof/kof MEFs showed a small but not statistically significant increase in telomere fusions compared to matched control MEFs.…”

Section: Resultsmentioning

confidence: 99%

Mice with reduced expression of the telomere‐associated protein Ft1 develop p53‐sensitive progeroid traits

et al. 2018

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SummaryHuman AKTIP and mouse Ft1 are orthologous ubiquitin E2 variant proteins involved in telomere maintenance and DNA replication. AKTIP also interacts with A‐ and B‐type lamins. These features suggest that Ft1 may be implicated in aging regulatory pathways. Here, we show that cells derived from hypomorph Ft1 mutant (Ft1 kof/kof) mice exhibit telomeric defects and that Ft1 kof/kof animals develop progeroid traits, including impaired growth, skeletal and skin defects, abnormal heart tissue, and sterility. We also demonstrate a genetic interaction between Ft1 and p53. The analysis of mice carrying mutations in both Ft1 and p53 (Ft1 kof/kof ; p53 ko/ko and Ft1 kof/kof ; p53 +/ko) showed that reduction in p53 rescues the progeroid traits of Ft1 mutants, suggesting that they are at least in part caused by a p53‐dependent DNA damage response. Conversely, Ft1 reduction alters lymphomagenesis in p53 mutant mice. These results identify Ft1 as a new player in the aging process and open the way to the analysis of its interactions with other progeria genes using the mouse model.

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Section: Resultsmentioning

confidence: 99%

Mice with reduced expression of the telomere‐associated protein Ft1 develop p53‐sensitive progeroid traits

et al. 2018

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“…To confirm this phenotype we immunostained the spreads with antibody against TERF1 (Supplementary Figure S6). TERF1 protein binds to repeats in telomeres and protects them against the degradation (79). We found the appearance of clusters of TERF1 clusters in places of telomere connections in ATZ-derived samples.…”

Section: Resultsmentioning

confidence: 99%

Exposure to the widely used herbicide atrazine results in deregulation of global tissue-specific RNA transcription in the third generation and is associated with a global decrease of histone trimethylation in mice

et al. 2016

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The epigenetic events imposed during germline reprogramming and affected by harmful exposure can be inherited and transferred to subsequent generations via gametes inheritance. In this study, we examine the transgenerational effects promoted by widely used herbicide atrazine (ATZ). We exposed pregnant outbred CD1 female mice and the male progeny was crossed for three generations with untreated females. We demonstrate here that exposure to ATZ affects meiosis, spermiogenesis and reduces the spermatozoa number in the third generation (F3) male mice. We suggest that changes in testis cell types originate from modified transcriptional network in undifferentiated spermatogonia. Importantly, exposure to ATZ dramatically increases the number of transcripts with novel transcription initiation sites, spliced variants and alternative polyadenylation sites. We found the global decrease in H3K4me3 occupancy in the third generation males. The regions with altered H3K4me3 occupancy in F3 ATZ-derived males correspond to altered H3K4me3 occupancy of F1 generation and 74% of changed peaks in F3 generation are associated with enhancers. The regions with altered H3K4me3 occupancy are enriched in SP family and WT1 transcription factor binding sites. Our data suggest that the embryonic exposure to ATZ affects the development and the changes induced by ATZ are transferred up to three generations.

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“…It has been proposed that these characteristics have important ramifications for human chromosome stability during DNA replication and for integration of mobile DNA elements (46). Being able to engineer hybrid yeast-vertebrate type telomeres in a genetically tractable system should allow us to further detail those evolutionary important mechanisms.…”

Section: Discussionmentioning

confidence: 99%

“…Recent evidence obtained in a variety of systems, including budding yeast, fission yeast, and mammalian cells, strongly suggests that the passage of the replication fork through telomeric repeats is a challenge and requires the presence of telomere repeat binding proteins and specialized helicases (45)(46)(47)(48). It has been proposed that these characteristics have important ramifications for human chromosome stability during DNA replication and for integration of mobile DNA elements (46).…”

Section: Discussionmentioning

confidence: 99%

Telomerase Is Required to Protect Chromosomes with Vertebrate-type T2AG3 3′ Ends in Saccharomyces cerevisiae

Bah

Gilson

Wellinger

2011

Journal of Biological Chemistry

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Telomeres containing vertebrate-type DNA repeats can be stably maintained in Saccharomyces cerevisiae cells. We show here that telomerase is required for growth of yeast cells containing these vertebrate-type telomeres. When present at the chromosome termini, these heterologous repeats elicit a DNA damage response and a certain deprotection of telomeres. The data also show that these phenotypes are due only to the terminal localization of the vertebrate repeats because if they are sandwiched between native yeast repeats, no phenotype is observed. Indeed and quite surprisingly, in this latter situation, telomeres are of virtually normal lengths, despite the presence of up to 50% of heterologous repeats. Furthermore, the presence of the distal vertebrate-type repeats can cause increased problems of the replication fork. These results show that in budding yeast the integrity of the 3 overhang is required for proper termination of telomere replication as well as protection.Specialized ribonucleoprotein complexes known as telomeres protect the natural ends of eukaryotic chromosomes. In the budding yeast Saccharomyces cerevisiae, telomeres are composed of an ϳ300-bp double-stranded (ds) 4 tract of irregular repeats, abbreviated TG 1-3 /C 1-3 A, and terminate with a 12-to 14-nt single-stranded (ss) 3Ј overhang made of the TG 1-3 motifs (1-3). In contrast, vertebrate telomeres contain a ds tract containing thousands of T 2 AG 3 /C 3 TA 2 repeats and terminate with a ss 3Ј overhang made of T 2 AG 3 motifs (2, 4, 5).The complete replication of linear eukaryotic chromosomes requires the de novo addition of telomeric repeats to chromosome ends by telomerase, a specialized reverse transcriptase (for reviews, see Refs. 6 -9). The core telomerase components are a reverse-transcriptase catalytic subunit and a RNA moiety. In yeast, these components are known as Est2p and TLC1, respectively (8). The telomerase RNA always contains a short region that is complementary to the G-rich strand of telomeric repeats, and that region is used as a template for repeat addition (7, 9).Telomerase invalidation leads to gradual telomere shortening and ultimately causes cells to stop dividing (7, 9, 10). Nevertheless, cellular backup mechanisms can maintain telomeres in the absence of telomerase and ultimately preserve genome integrity. In this mode of telomere maintenance, which is known as alternative lengthening of telomeres in human cells, and survivor mode in Saccharomyces cerevisiae, telomeric DNA is maintained via homologous recombination-based mechanisms (11,12).By differentiating chromosomal ends from internal ds breaks, telomeres also prevent chromosomal ends from eliciting DNA damage checkpoint activation and protect telomeres from inappropriate DNA repair activity. Binding of the multiprotein complex shelterin is essential for both protecting and maintaining the length of mammalian telomeres (13,14). Rap1p, one of the several proteins associated with similar functions at budding yeast telomeres, binds directly to ds telomeric repeats ...

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Mammalian Telomeres Resemble Fragile Sites and Require TRF1 for Efficient Replication

Cited by 870 publications

References 69 publications

Mice with reduced expression of the telomere‐associated protein Ft1 develop p53‐sensitive progeroid traits

Mice with reduced expression of the telomere‐associated protein Ft1 develop p53‐sensitive progeroid traits

Exposure to the widely used herbicide atrazine results in deregulation of global tissue-specific RNA transcription in the third generation and is associated with a global decrease of histone trimethylation in mice

Telomerase Is Required to Protect Chromosomes with Vertebrate-type T2AG3 3′ Ends in Saccharomyces cerevisiae

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