Completed Genetics & Molecular Biology Cells, Biochemistry & Physiology

Molecular mechanisms of telomere protection and poly(ADP-ribosyl)ation-regulated telomere length homeostasis

Funder Wellcome Charity-funded
Recipient organisation Institute of Cancer Research
Funding £1.7M
Period Apr 2019 — Apr 2024

In plain English

AI plain-English summary

Every time a cell divides, it must solve a puzzle: how to copy the very ends of its chromosomes without triggering a DNA repair system that would mistake those ends for broken DNA and fuse them together. This project investigates the molecular machinery that solves that puzzle—a six-protein complex called Shelterin that caps chromosome ends, and an enzyme called tankyrase that temporarily loosens that cap to allow an enzyme called telomerase to extend the telomeres. The researchers will use cryo-electron microscopy to visualise these molecules at near-atomic resolution, combined with biochemical and cell-based experiments. The work is fundamental science: it addresses a basic question about how cells maintain genomic stability. Understanding this mechanism matters because mutations in Shelterin and telomerase components are linked to telomere disorders—rare conditions causing bone marrow failure and pulmonary fibrosis—and to many cancers, which reactivate telomerase to achieve unlimited division. A clearer picture of how tankyrase remodels Shelterin without triggering a DNA damage response could eventually inform strategies for selectively blocking telomere extension in cancer cells or preserving it in stem cells.

View original technical description
Telomeres, the ends of linear chromosomes, face two unique challenges. The first, the end protection problem, arises from the resemblance of chromosome ends to DNA double-strand breaks, which elsewhere in the genome trigger a rapid DNA damage response that needs to be averted at telomeres. The second, the end replication problem, refers to the gradual loss of telomeric DNA with every round of DNA replication. Telomere end protection is achieved by the six-membered telomeric Shelterin complex. Shelterin mutations in cancer and telomere disorders illustrate the importance of the complex in telomere maintenance. Homeostatic telomere extension (in stem and most cancer cells) is achieved by telomerase and a Shelterin-dependent telomere length-sensing mechanism. However, end protection collaterally impedes the access of telomerase to telomeres, a dilemma that in human cells is solved by the poly(ADP-ribose)polymerase (PARP) tankyrase, which remodels the Shelterin complex. The mechanism of telomere protection and length maintenance remains incompletely understood. Moreover, how tankyrase remodels the Shelterin complex to enable telomere extension without triggering a DNA damage response is unknown. We aim to unravel the mechanisms of telomere protection and length homeostasis by combining single-particle cryo-electron microscopy with biochemical and biophysical assays as well as functional studies in mammalian cells.

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Researchers

Sebastian Guettler (EPMC Awardee)

Related Research

Grants with similar aims, by meaning.

Composition and function of telomeric multi-protein complexes and their regulation by ADP-ribosylation
The Shelterin-chromatin interplay in telomere homeostasis and genome stability
Single-molecule studies of T-loop formation and telomerase recruitment at telomeres
Telomere Biology Lab
The role of DNA binding and nucleolytic activities within mammalian telomerase

Original classification

Investigator Award in Science

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