Sjoerd Wanrooij - Assistant Professor
Molecular mechanism of DNA repair and replication in human mitochondria
Mitochondrial DNA and disease
Mitochondrial DNA (mtDNA) dysfunction results in a broad range of human disorders. Alterations in the mitochondrial DNA give rise to a variety of neuromuscular symptoms and accumulate in inherited mitochondrial disorders, but also in the affected tissues of Parkinsons’s disease patients. In spite of their medical relevance, little is known about the mechanisms by which mtDNA mutations/deletions form, which hampers the development of treatments. We investigate mtDNA maintenance in order to better understand the underlying causes of such disease states. The research consists of in vitro biochemical experiments in combination with cell biological approaches to verify any in vivo relevance.
Mara Doimo, Post Doc
Kazutoshi Kasho, Post Doc
Gorazd Stojkovic, Post Doc
Annika Pfeiffer, Post Doc
Sonja Stenmark, Senior research engineer
Josefin Forslund, Ph.D.-student
Valentin L’hôte, Master's-student
Forslund JME, Pfeiffer A, Stojkovič G, Wanrooij PH and Wanrooij S. The presence of rNTPs decreases the speed of mitochondrial DNA replication. (2018) PLOS Genetics In press.
Torregrosa-Muñumer R+, Forslund JME+, Goffart S, Pfeiffer A, Stojkovič G, Carvalho G, Al-Furoukh N, Blanco L, Wanrooij S+, Pohjoismäki JLO+. (2017): PrimPol is required for replication re-initiation after mitochondrial DNA damage. Proc Natl Acad Sci 114(43):11398-11403. + shared first and last author
Wanrooij PH, Engqvist MKM, Forslund JME, Navarrete C, Nilsson AK, Sedman J, Wanrooij S, Clausen AR and Chabes A (2017). No repair of ribonucleotides misincorporated into yeast mitochondrial DNA. Proc Natl Acad Sci 114(47):12466-12471.
Boldinova EO+, Stojkovič G+, Khairullin R, Wanrooij S+ and Makarova AV+ (2017): Optimization of the expression, purification and polymerase activity reaction conditions of recombinant human PrimPol. PloS One 12(9):e0184489 +shared first and last author
Cooper HM, Yang Y, Ylikallio E, Khairullin R, Woldegebriel R, Kai-Lan L, Euro L, Palin E, Wolf A, Trokovic R, Isohanni P, Kaakkola S, Auranen M, Lönnqvist T, Wanrooij S and Tyynismaa H (2017): ATPase-deficient mitochondrial inner membrane protein ATAD3A disturbs mitochondrial dynamics in dominant hereditary spastic paraplegia. Human Mol Genet 26(8):1432-1443.
Boldinova EO, Wanrooij PH, Shilkin ES, Wanrooij S+ and Makarova AV+ (2017): DNA damage tolerance by eukaryotic DNA polymerase and primase PrimPol. Int J Mol Sci 18(7) +shared last author
Gorazd Stojkovič, Alena V. Makarova, Paulina H. Wanrooij, Josefin Forslund, Peter M. Burgers and Sjoerd Wanrooij (2016): Oxidative DNA damage stalls the human mitochondrial replisome. Scientific Reports 6:28942.
Miralles Fusté J, Shi Y, Wanrooij S, Zhu X, Jemt E, Persson Ö, Sabouri N, Gustafsson CM, Falkenberg M (2014). In vivo occupancy of mitochondrial single-stranded DNA binding protein supports the strand displacement mode of DNA replication PLoS Genet. 4;10(12):e1004832.
Shi Y, Dierckx A, Wanrooij PH, Wanrooij S, Larsson NG, Wilhelmsson LM, Falkenberg M and Gustafsson CM (2012): Mammalian transcription factor A is a core component of the mitochondrial transcription machinery. Proc Natl Acad Sci USA 109: 16510-16515.
Wanrooij S, Miralles Fuste J, Stewart JB, Wanrooij PH, Samuelsson T, Larsson NG, Gustafsson CM and Falkenberg M (2012): In vivo mutagenesis reveals that OriL is essential for mitochondrial DNA replication. EMBO Rep 13: 1130-1137.
Wanrooij S, Falkenberg M (2010). The human mitochondrial replication fork in health and disease. Biochim Biophys Acta 1797: 1378-1388.
Fuste JM+, Wanrooij S+, Jemt E, Granycome EG, Cluett TJ, Shi Y, Atanassova N, Holt IJ, Gustafsson CM and Falkenberg M (2010): Mitochondrial RNA polymerase is needed for activation of the origin of light-strand DNA replication. Mol Cell 37: 67-78. +Shared first author
Wanrooij S, Fuste JM, Farge G, Shi Y, Gustafsson CM and Falkenberg M (2008): Human mitochondrial RNA polymerase primes lagging-strand DNA synthesis in vitro. Proc Natl Acad Sci USA 105: 11122-11127. ´
Krishnan KJ, Reeve AK, Samuels DC, Chinnery PF, Blackwood JK, Taylor RW, Wanrooij S, Spelbrink JN, Lightowlers RN and Turnbull DM (2008): What causes mitochondrial DNA deletions in human cells? Nat Genet 40: 275-279.
Wanrooij S, Goffart S, Pohjoismäki JLO, Yasukawa T and Spelbrink JN (2007): Expression of catalytic mutants of the mtDNA helicase and polymerase POLG causes distinct replication stalling phenotypes. Nucleic Acids Res 35: 3238-3251
Wanrooij S, Luoma P, van Goethem G, van Broeckhoven C, Suomalainen A and Spelbrink JN (2004): Twinkle and POLG defects enhance age-dependent accumulation of mutations in the control region of mtDNA. Nucleic Acids Res 32: 3053-3064.
Spelbrink JN, Li FY, Tiranti V, Nikali K, Yuan QP, Tariq M, Wanrooij S, Garrido N, Comi G, Morandi L, Santoro L, Toscano A, Fabrizi GM, Croxen R, Beeson D, Poulton J, Suomalainen A, Jacobs HT, Zeviani M and Larsson C (2001) Human mitochondrial DNA deletions associated with mutations in the gene encoding Twinkle, a phage T7 gene 4-like protein localized in mitochondria. Nat Genet 28: 223-231.