MRC DiMeN Doctoral Training Partnership: Stopping premature ageing: Investigating the role of actomyosin mediated nuclear force feedback in cell homeostasis.

Why do some cells age too early? Hutchinson–Gilford Progeria Syndrome (HGPS) is a genetic disorder that causes premature ageing and leads to an average life expectancy of 15 years. It results from a mutation in the nuclear lamina gene LMNA, which compromises the mechanical integrity of the nucleus. Our recent findings show that HGPS patient cells experience abnormally high cytoskeletal tension, making their nuclei mechanically fragile and prone to DNA damage.

In healthy cells, mechanical feedback between the nucleus and cytoskeleton prevents damaging levels of force. We have discovered that this protective pathway involves two key proteins—Sun2, located in the nuclear envelope, and Rnd3, a regulator of actomyosin tension. When forces rise, Sun2 and Rnd3 coordinate to reduce tension and safeguard the genome. In HGPS cells, this feedback loop fails, leading to persistent stress, nuclear rupture, and cell death. This project will explore the mechanism behind the mechanical vulnerability of HGPS patient cells.

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