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Regulation of mitochondrial gene expression

  • Full or part time
  • Application Deadline
    Saturday, June 30, 2018
  • Competition Funded PhD Project (Students Worldwide)
    Competition Funded PhD Project (Students Worldwide)

Project Description

The key objective of this PhD project is to study nuclear-encoded proteins involved in mitochondrial (mt-) RNA metabolism, in order to understand how their dysfunction is linked to human mitochondrial pathologies.

The human mitochondrial genome (mtDNA) codes for several structural components of the oxidative phosphorylation system (OxPhos) and RNA components for intra-mitochondrial protein synthesis. Therefore, mitochondria have evolved unique and highly specialised mechanisms to express the mtDNA-encoded genes. The mitochondrial rRNAs, mRNAs and tRNAs are transcribed as polycistronic units. Following the endonucleolytic processing, individual transcripts undergo post-transcriptional maturation. Several nucleotides of mt-rRNAs are modified to facilitate mitoribosome biogenesis and function, a poly(A) tail is added to mt-mRNAs and mt-tRNAs undergo extensive post-transcriptional modifications, before being aminoacylated with a cognate amino acid. Turnover and surveillance pathways have also been described for mammalian mt-RNA [1].

Establishing how defects in these processes contribute to human mitochondrial disease constitutes a major challenge. Our recent studies have brought many important insights into the regulation of mtDNA expression. We have identified and characterised a number of novel factors, either by basic research approaches, or through the study of patients with mitochondrial disorders. Currently, we try to understand the regulation of mammalian mitochondrial gene expression focussing on the following fundamental processes:
• Polyadenylation of mitochondrial RNA [2]
• Post-transcriptional modification (“epitranscriptomics”) of mitochondrial RNA [3, 4]
• Biogenesis of mitochondrial ribosome [5]

In our research, we use the following latest tools and techniques: next generation RNA sequencing (RNA-Seq) to characterise mt-RNA abundance, processing and maturation [2,3]; HITS-CLIP to study RNA-protein interactions [3]; SILAC-based proteomics and RNASeq-based ribosome profiling for analyses of mitochondrial translation and mitochondrial ribosome [2].



Funding Notes

(Full funding available for UK and EU applicants; others can apply if they wish)

References

1. Pearce SF, Rebelo-Guiomar P, D'Souza AR, Powell CA, Van Haute L, Minczuk M. (2017) Regulation of Mammalian Mitochondrial Gene Expression: Recent Advances. Trends Biochem Sci. 42, 625-639

2. Pearce SF, Rorbach J, Van Haute L, D'Souza AR, Rebelo-Guiomar P, Powell CA, Brierley I, Firth AE & Minczuk M. (2017) Maturation of selected human mitochondrial tRNAs requires deadenylation. eLife 6, e2759

3. Van Haute L, Dietmann S, Kremer L, Hussain S, Pearce SF, Powell CA, Rorbach J, Lantaff R, Blanco S, Sauer S, Kotzaeridou U, Hoffmann GF, Memari Y, Kolb-Kokocinski A, Durbin R, Mayr JA, Frye M, Prokisch H & Minczuk M. (2016) Deficient methylation and formylation of mt-tRNA(Met) wobble cytosine in a patient carrying mutations in NSUN3. Nature Commun. 7, 12039

4. Garone C, D'Souza AR, Dallabona C, Lodi T, Rebelo-Guiomar P, Rorbach J, Donati MA, Procopio E, Montomoli M, Guerrini R, Zeviani M, Calvo SE, Mootha VK, DiMauro S, Ferrero I, Minczuk M. (2017) Defective mitochondrial rRNA methyltransferase MRM2 causes MELAS-like clinical syndrome. Hum Mol Genet. Published online.

5. Rorbach J, Gao F, Powell CA, D'Souza A, Lightowlers RN, Minczuk M & Chrzanowska-Lightowlers Z (2016) Human mitochondrial ribosomes can switch their structural RNA composition. Proc Natl Acad Sci U S A 113, 12198-12201

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