Resolution of telomere associations by TRF1 cleavage in mouse embryonic stem cells

Lisaingo, Kathleen; Uringa, Evert-Jan; Lansdorp, Peter M.

doi:10.1091/mbc.e13-10-0564

Cited by 12 publications

(10 citation statements)

References 52 publications

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“…Interestingly, we also observed the localization of TRF1 connecting telomeres of two or more chromosomes (Figure 2Bb white arrow) or in fused telomeres (Figure 2Bb, blue arrow). This pattern of localization has been described at telomeres when unbalanced levels of TRF1 are present (Lisaingo et al 2014) and resembled the telomeric defects we previously reported using FISH (Martinerie et al 2014). These results showed that levels of TRF1 at the telomeres were not affected by deficiency of E-type cyclins, but its localization pattern might be affected, forming stretches of DNA and bridges between chromosomes.…”

Section: Resultssupporting

confidence: 87%

“…Although TRF1 does not contribute significantly to the end protection functions of the Shelterin complex (Zimmermann et al 2014), it plays a key role in maintaining telomere length, and in the formation of telomere associations in mitosis and meiosis (Cooper et al 1998; Miller et al 2006). It has been further shown that unbalanced levels of TRF1 in telomeres, produced by experimental overexpression or observed in cancer cells, results in telomeric bridges and aggregates containing TRF1 protein and telomeric DNA (Lisaingo et al 2014; Munoz et al 2009). We have previously reported that one of the most striking meiotic phenotypes observed in E-type cyclin deficient spermatocytes is a high frequency of telomeric bridges between non-homologous chromosomes (Martinerie et al 2014).…”

Section: Resultsmentioning

confidence: 99%

“…Indeed, when chromosome ends retain insufficient TRF2 to inhibit the DNA damage repair (DDR) response and end joining, γ-H2AX foci form at the chromosome ends, telomeres are shortened, and chromosome fusions occur (Cesare et al 2013). In addition, when only TRF1 is present at telomeric tracts of DNA, or when it is overexpressed in cells, the telomeres lose their individuality, with pairing of the telomeric sequences and association of different telomeres (Griffith et al 1998; Lisaingo et al 2014). …”

Section: Introductionmentioning

confidence: 99%

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E-type cyclins modulate telomere integrity in mammalian male meiosis

2015

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We have shown that E-type cyclins are key regulators of mammalian male meiosis. Depletion of cyclin E2 reduced fertility in male mice due to meiotic defects, involving abnormal pairing and synapsis, unrepaired DNA, and loss of telomere structure. These defects were exacerbated by additional loss of cyclin E1, and complete absence of both E-type cyclins produces a meiotic catastrophe. Here, we investigated the involvement of E-type cyclins in maintaining telomere integrity in male meiosis. Spermatocytes lacking cyclin E2 and one E1 allele (E1+/−E2−/−) displayed a high rate of telomere abnormalities but can progress to pachytene and diplotene stages. We show that their telomeres exhibited an aberrant DNA damage repair response during pachynema and that the Shelterin-complex proteins TRF2 and RAP2 were significantly decreased in the proximal telomeres. Moreover, the insufficient level of these proteins correlated with an increase of γ-H2AX foci in the affected telomeres, and resulted in telomere associations involving TRF1 and telomere detachment in later prophase-I stages. These results suggest that E-type cyclins are key modulators of telomere integrity during meiosis by, at least in part, maintaining the balance of Shelterin-complex proteins, and uncover a novel role of E-type cyclins in regulating chromosome structure during male meiosis.

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Section: Resultssupporting

confidence: 87%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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E-type cyclins modulate telomere integrity in mammalian male meiosis

2015

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“…Anaphase bridges are found among cells exhibiting impaired telomere homeostasis [39][40][41][42] and defective DNA DSB repair. [36][37][38][39][40][41][42][43][44][45][46][47][48][49] RINT1 is known to be involved in both pathways through interaction with p130 15 or Rad50. 14 The structure of chromosome fusion in the Rint1-deficient cells supports the hypothesis of defective DSB repair (Figures 4c and d).…”

Section: Discussionmentioning

confidence: 99%

Rint1 inactivation triggers genomic instability, ER stress and autophagy inhibition in the brain

et al. 2015

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Endoplasmic reticulum (ER) stress, defective autophagy and genomic instability in the central nervous system are often associated with severe developmental defects and neurodegeneration. Here, we reveal the role played by Rint1 in these different biological pathways to ensure normal development of the central nervous system and to prevent neurodegeneration. We found that inactivation of Rint1 in neuroprogenitors led to death at birth. Depletion of Rint1 caused genomic instability due to chromosome fusion in dividing cells. Furthermore, Rint1 deletion in developing brain promotes the disruption of ER and Cis/Trans Golgi homeostasis in neurons, followed by ER-stress increase. Interestingly, Rint1 deficiency was also associated with the inhibition of the autophagosome clearance. Altogether, our findings highlight the crucial roles of Rint1 in vivo in genomic stability maintenance, as well as in prevention of ER stress and autophagy.

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“…Increased telomere length may promote melanoma formation by delaying telomere‐driven senescence in melanoma precursor lesions, such as ‘dysplastic’ nevi. Increased telomere length may itself drive telomere genomic instability by promoting chromosome mis‐segregation and aneuploidy through effects on mitosis . Finally, heterogeneous or increased telomere length might simply be a marker of telomere uncapping, which would be the primary driver of genomic instability and aneuploidy .…”

Section: Discussionmentioning

confidence: 99%

A primary melanoma and its asynchronous metastasis highlight the role of BRAF, CDKN2A, and TERT

et al. 2014

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Background Alterations in pathways including BRAF, CDKN2A, and TERT contribute to the development of melanoma, but the sequence in which the genetic alterations occur and their prognostic significance remain unclear. To clarify the role of these pathways, we analyzed a primary melanoma and its metastasis. Methods Immunohistochemistry for BRAF-V600E, Sanger sequencing of BRAF and the TERT promoter, fluorescence in-situ hybridization, and telomere analyses were performed on a primary melanoma and its asynchronous cerebellar metastasis. Using the log-rank test and Cox-proportional model, the cancer genome atlas (TCGA) cohort of melanomas was analyzed for the effect of BRAF mutation and CDKN2A loss on survival. Results The primary melanoma expressed mutant BRAF-V600E and possessed a homozygous deletion of CDKN2A. In addition to these early defects, the metastatic lesion also possessed evidence of aneuploidy and an activating mutation of the TERT promoter. In the TCGA melanoma cohort, there was a non-significant trend towards poor prognosis in early stage cutaneous melanoma patients with concomitant BRAF mutation and CDKN2A loss. Conclusion BRAF mutation and CDKN2A loss occurred early and TERT promoter mutation later in a case of lethal metastatic melanoma. The effects of these pathways on survival warrant further investigation in early stage cutaneous melanoma patients.

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Resolution of telomere associations by TRF1 cleavage in mouse embryonic stem cells

Cited by 12 publications

References 52 publications

E-type cyclins modulate telomere integrity in mammalian male meiosis

E-type cyclins modulate telomere integrity in mammalian male meiosis

Rint1 inactivation triggers genomic instability, ER stress and autophagy inhibition in the brain

A primary melanoma and its asynchronous metastasis highlight the role of BRAF, CDKN2A, and TERT

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