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Nuclear envelope attachment and dynamics of Human telomeres - unravelling nuclear organization

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The role telomeres play in post-mitotic nuclear assembly

Characterising the interaction between telomeres and the ‘nuclear envelope’ of cells could advance our understanding of aging, cancer and rare genetic diseases.

Fundamental Research icon Fundamental Research

The genome, containing the DNA instructions to make an organism, is stored in the cell nucleus. The nuclear envelope, a membrane surrounding the nucleus and separating it from the rest of the cell, plays a key role in organising the genome efficiently. The genome itself comprises linear chromosomes carrying the genetic cargo, each ‘book-ended’ by protective structures called telomeres. These function like a molecular clock. They mark the aging process as they shorten as cells divide, until they reach a critical size when cell division stops. The EU-funded TeloHOOK project set out to study the role telomeres might play in the distribution of chromosome within the nucleus of human cells, and so their impact on aging and disease. As project coordinator Laure Crabbe explains: “In organisms like yeast and worms, telomeres are ‘anchored’ to the nuclear envelope. It wasn’t clear whether this also happened in humans, and with what impact.” TeloHOOK developed a new technique, MadID, to map protein-DNA interactions, helping the team identify proteins involved in telomere tethering to the nuclear envelope. A genome engineered cell line then allowed the team to microscopically track telomere dynamics and computer model it. “These techniques allowed us to uncover a previously unknown role that telomeres play in cell mitosis and to shed light on what happens when things go wrong,” summarises Crabbe formerly of the French National Centre for Scientific Research, the project host. MadID is now available to the research community, along with the plasmids needed.

Tracking telltale proteins

TeloHOOK was particularly interested in learning more about how the interaction between telomeres and the cell nuclear envelope influenced mitosis or cell division, particularly a stage called ‘post-mitotic nuclear assembly’. The team’s newly developed Methyl Adenine Identification (MadID) were first mapped in high resolution telomere/nuclear envelope contact sites. With the help of mass spectrometry, the team then identified specific proteins involved in telomere/nuclear envelope interaction and those that seemed connected to telomeres during ‘post-mitotic nuclear assembly’. To explore telomere organisation in the nucleus in detail, the team used a combination of live cell and super resolution microscopy and 3D modelling. They used CRISPR-Cas9 to tag a protein that specifically binds to telomeres, with a fluorescent probe, making the telomeres trackable in live cells using Airyscan confocal microscopy. Being able to follow their movement allowed the researchers to study and model their functioning. “We discovered that after the cell’s nuclear envelope breaks down to release its chromosomes during mitosis, telomeres seem to drive the reassembly of that nuclear envelope,” explains Crabbe. The team were also interested in what happens when nuclear envelope integrity is compromised and so looked to the premature aging syndrome, HGPS (Hutchinson–Gilford progeria syndrome). “We saw how disorganised telomeres in the nucleus compromises cellular maintenance, accelerating telomere shortening, which prompts biological aspects of aging, normally experienced later,” adds Crabbe.

The future of the high-risk, high-gain approach

A genome organised to ensure that its instructions can be read properly, is a prerequisite for cellular function in any tissue of any living organism. Alongside a contribution to basic research, TeloHOOK’s results have implications for aging research and treatment possibilities for cancer and rare genetic diseases, like HGPS. Crabbe suggests that some of the proteins identified in the screening process, and the underlying mechanisms of their interaction with telomeres, be further studied. As Crabbe says: “For example, for the telomeres that bind to a protein from the nuclear envelope during postmitotic nuclear assembly: what happens if the protein is depleted or overexpressed? We don’t know.”

Keywords

TeloHOOK, telomere, chromosome, genetic, cell, nucleus, mitosis, Hutchinson–Gilford progeria syndrome, genome, DNA, aging, cancer

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