Community Research and Development Information Service - CORDIS


REPMIT Report Summary

Project ID: 261248
Funded under: FP7-IDEAS-ERC
Country: Sweden


In the current project we have investigated basic aspects of mitochondrial DNA replication. We have contributed with important new insights into the process of mitochondrial DNA replication initiation. We have demonstrated how primer formation is directed by a G-quadruplex structure in DNA at a conserved sequence element termed CSB II (Wanrooij et al, Nucleic Acids Res. 2012 Nov 1;40(20):10334-44). We have also demonstrated that mtDNA replication is regulated by premature termination at the end of the so called control region and that this regulation is dependent on the loading/unloading of the replicative mtDNA helicase TWINKLE (Jemt et al, Nucleic Acids Res. 2015 Oct 30;43(19):9262-75). In addition, we have performed work to demonstrate how mtDNA replication is terminated at OriH once DNA has progressed full circle (Uhler et al, Nucleic Acids Res. 2016 May 24. pii: gkw468.).

We have also performed work to characterize the structure and function of the nucleoid, i.e. mitochondrial DNA packaged together with mitochondrial proteins. We have characterized the nucleoid with microscopy and functional assays, which has resulted in a detailed structural understanding of the mtDNA nucleoid. We have also demonstrated how DNA packaging by a major nucleoid constituent the TFAM protein, can regulate mitochondrial DNA replication and transcription (Mehmedovic et al, Cell report 2015. Jul 10;8(1):66-74). In addition, our studies revealed how another key component of the nucleoid, the mitochondrial single-stranded DNA-binding protein (mtSSB) regulates primer formation and directs mtDNA replication (Fuste et al. Plos genetics 2014, Dec 4;10(12):e1004832)

In the project, we have also analyzed a number of disease causing amino acid changes in the mitochondrial DNA polymerase gamma. The project has generated new insights into the structure-function of this important polymerase. We have also elucidated the interplay between the proofreading activity of DNA polymerase gamma and the ability of the polymerase to generate ligatable ends (Bratic Nat Commun. 2015 Nov 10;6:8808; and Macao Nat Commun. 2015 Jun 22;6:7303).

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