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Role of RNA decay SKI complex in telomere maintenance, DNA damage response and human THES syndrome.


Project Description

During DNA replication multiple factors are transiently recruited to facilitate the movement of the replisome, especially when the replication forks are hindered by DNA secondary structures (T-loop, G4, RNA/DNA hybrids) or protein/DNA complexes (Zimmermann et al. 2014, G&D 28, 2477; Vannier et al. 2013, Science 342, 239). We have used PICh (Dejardin and Kingston, 2009, Cell 136, 175) to identify new factors specifically recruited at telomeres during the different stages of the cell cycle. We identified SKIV2L and its associated factors to be a novel G2 telomere-binding complex. Depletion of SKIV2L, which bears the RNA helicase activity of the complex, leads to the activation of the DNA Damage Response (ATM and H2AX phosphorylations) at telomeres and is associated with telomeric abnormalities. We now want to identify the molecular mechanism and function of SKIV2L and SKI complex at telomeres. We will use a combination of molecular and cell biology but also animal work to dissect its function in telomere maintenance and in trichohepatoenteric syndrome (THES) in humans. This syndrome is a rare autosomal recessive disorder. Patients have an average lifespan of 6 months, they present intrauterine growth retardation, intractable diarrhoea and immunodeficiency among other symptoms (Fabre et al. 2012, Am J Hum Genet 90, 689). Although the molecular mechanism causing the disease is unknown, THES is proposed to be a consequence of an accumulation of RNA disturbing general cellular processes (Fabre et al. 2018, Am J Med Genet A 176, 727). Therefore, it is essential to understand the relevance of telomere maintenance in the development of this disorder. First, we will complement our deficient cell lines with wild type and SKIV2L patient mutations using transient transfections to confirm that the different phenotypes are specifically dependent on SKIV2L and the SKI complex. Secondly, we will produce a conditional SKIV2L mouse model in order to investigate the function of SKIV2L on ageing and on the immune system.

To Apply: Please visit our website (https://lms.mrc.ac.uk/study-here/phd-studentships/lms-3-5yr-studentships/) to download an application form.

Funding Notes

This project is one of multiple available projects potentially funded by the MRC. If successful the studentship would cover all tuition fee payments and includes a tax-free stipend amounting to £21,000pa (paid in monthly installments directly to the student) for 3.5 years.

Whilst this funding is available to students worldwide, due to the higher tuition fee rate of overseas students competition is higher and so only exceptional OS applicants will be considered.

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