The Long Linker Region of Telomere-Binding Protein TRF2 Is Responsible for Interactions with Lamins

Travina, A. O.; Ilicheva, Nadya V; Mittenberg, A. G.; Shabelnikov, Sergey; Kotova, A.; Podgornaya, O. I.

doi:10.3390/ijms22073293

Cited by 10 publications

(6 citation statements)

References 82 publications

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“…However, how telomeres are anchored at the nuclear periphery is still unclear. There is evidence for an association of telomeres with the nuclear matrix ( 58 , 87 ) as well as for interactions between lamins and shelterin proteins ( 88 , 89 ). On the other hand, it was shown that such interactions may be restricted to a brief time window in late mitosis/early G1 phase while being minimal or absent during the rest of interphase ( 84 ).…”

Section: Discussionmentioning

confidence: 99%

Ultrastructure and nuclear architecture of telomeric chromatin revealed by correlative light and electron microscopy

Hübner

Otter

Ahsan

et al. 2022

Nucleic Acids Research

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Telomeres, the ends of linear chromosomes, are composed of repetitive DNA sequences, histones and a protein complex called shelterin. How DNA is packaged at telomeres is an outstanding question in the field with significant implications for human health and disease. Here, we studied the architecture of telomeres and their spatial association with other chromatin domains in different cell types using correlative light and electron microscopy. To this end, the shelterin protein TRF1 or TRF2 was fused in tandem to eGFP and the peroxidase APEX2, which provided a selective and electron-dense label to interrogate telomere organization by transmission electron microscopy, electron tomography and scanning electron microscopy. Together, our work reveals, for the first time, ultrastructural insight into telomere architecture. We show that telomeres are composed of a dense and highly compacted mesh of chromatin fibres. In addition, we identify marked differences in telomere size, shape and chromatin compaction between cancer and non-cancer cells and show that telomeres are in direct contact with other heterochromatin regions. Our work resolves the internal architecture of telomeres with unprecedented resolution and advances our understanding of how telomeres are organized in situ.

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Section: Discussionmentioning

confidence: 99%

Ultrastructure and nuclear architecture of telomeric chromatin revealed by correlative light and electron microscopy

Hübner

Otter

Ahsan

et al. 2022

Nucleic Acids Research

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“…We further confirmed the interaction of endogenous lamin B1 with the TRF2 longer isoform by PLA assay (Figure 6C ). Very recently, the linker region of TRF2 (also referred as the Hinge domain ( 8 ), located between the TRFH and Myb domains, has been reported to interact with lamins, including lamin B1, by co-immunoprecipitation from enriched nuclear lamina extracts ( 75 ). In accordance with this paper, by PLA assay, we found that the linker region interacts with the endogenous lamin B1 protein in situ in cells transfected with a vector expressing the TRF2 linker fragment (Figure 6D ).…”

Section: Resultsmentioning

confidence: 99%

Increase in lamin B1 promotes telomere instability by disrupting the shelterin complex in human cells

Pennarun

Picotto

Etourneaud

et al. 2021

Nucleic Acids Research

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Telomere maintenance is essential to preserve genomic stability and involves telomere-specific proteins, DNA replication and repair proteins. Lamins are key components of the nuclear envelope and play numerous roles, including maintenance of the nuclear integrity, regulation of transcription, and DNA replication. Elevated levels of lamin B1, one of the major lamins, have been observed in some human pathologies and several cancers. Yet, the effect of lamin B1 dysregulation on telomere maintenance remains unknown. Here, we unveil that lamin B1 overexpression drives telomere instability through the disruption of the shelterin complex. Indeed, lamin B1 dysregulation leads to an increase in telomere dysfunction-induced foci, telomeric fusions and telomere losses in human cells. Telomere aberrations were preceded by mislocalizations of TRF2 and its binding partner RAP1. Interestingly, we identified new interactions between lamin B1 and these shelterin proteins, which are strongly enhanced at the nuclear periphery upon lamin B1 overexpression. Importantly, chromosomal fusions induced by lamin B1 in excess were rescued by TRF2 overexpression. These data indicated that lamin B1 overexpression triggers telomere instability through a mislocalization of TRF2. Altogether our results point to lamin B1 as a new interacting partner of TRF2, that is involved in telomere stability.

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“…These ITLs are suggested to play a role in telomere protection and/or stabilization [ 113 , 166 ]. It was recently reported that the linker region of TRF2 may be involved in lamin A-TRF2 association [ 167 ]. However, a previous study reported that the dominant-negative form of TRF2 (TRF2 ΔBΔM ), which can no longer bind telomere [ 113 ], but still contains the linker region, lacks an interaction with lamin A, suggesting that lamin A is preferentially associated with DNA-bound TRF2.…”

Section: Focus On Lamina and Telomere Maintenancementioning

confidence: 99%

Close Ties between the Nuclear Envelope and Mammalian Telomeres: Give Me Shelter

Pennarun

Picotto

Bertrand

2023

Genes

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The nuclear envelope (NE) in eukaryotic cells is essential to provide a protective compartment for the genome. Beside its role in connecting the nucleus with the cytoplasm, the NE has numerous important functions including chromatin organization, DNA replication and repair. NE alterations have been linked to different human diseases, such as laminopathies, and are a hallmark of cancer cells. Telomeres, the ends of eukaryotic chromosomes, are crucial for preserving genome stability. Their maintenance involves specific telomeric proteins, repair proteins and several additional factors, including NE proteins. Links between telomere maintenance and the NE have been well established in yeast, in which telomere tethering to the NE is critical for their preservation and beyond. For a long time, in mammalian cells, except during meiosis, telomeres were thought to be randomly localized throughout the nucleus, but recent advances have uncovered close ties between mammalian telomeres and the NE that play important roles for maintaining genome integrity. In this review, we will summarize these connections, with a special focus on telomere dynamics and the nuclear lamina, one of the main NE components, and discuss the evolutionary conservation of these mechanisms.

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The Long Linker Region of Telomere-Binding Protein TRF2 Is Responsible for Interactions with Lamins

Cited by 10 publications

References 82 publications

Ultrastructure and nuclear architecture of telomeric chromatin revealed by correlative light and electron microscopy

Ultrastructure and nuclear architecture of telomeric chromatin revealed by correlative light and electron microscopy

Increase in lamin B1 promotes telomere instability by disrupting the shelterin complex in human cells

Close Ties between the Nuclear Envelope and Mammalian Telomeres: Give Me Shelter

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