Inhibitors of mitochondrial gene transcription
The laboratory investigates the mechanisms of mammalian mitochondrial transcription. The levels of mitochondrial transcription are regulated in response to the overall respiratory needs of the eukaryotic cell, but the molecular mechanisms behind this regulation are poorly understood. Much of the work is performed using in vitro biochemistry and a reconstituted system for mammalian mtDNA transcription, containing only a promoter containing DNA fragment, and recombinant proteins. One of our areas of interest is the MTERF family of proteins. These proteins regulate mitochondrial gene expression at many different levels, including transcription initiation, transcription termination, and during protein translation. We are also studying DNA sequence dependent transcription termination in mitochondria. In our work, we have seen that a G-quadruplex structure formed in nascent RNA during transcription can stimulate termination. The mechanism is reminiscent of Rho-independent transcription termination in prokaryotes, with the exception that a G-quadruplex structure replaces the hairpin loop formed in bacterial mRNA during transcription of terminator sequences.
Shi Y, Posse V, Zhu X, Hyvärinen AK, Jacobs HT, Falkenberg M, Gustafsson CM. (2016) Mitochondrial transcription termination factor 1 directs polar replication fork pausing. Nucleic Acids Res. 44(12):5732-42. doi: 10.1093/nar/gkw302. Epub 2016 Apr 25.
Stewart JB, Alaei-Mahabadi B, Sabarinathan R, Samuelsson T, Gorodkin J, Gustafsson CM, Larsson E. (2015) Simultaneous DNA and RNA Mapping of Somatic Mitochondrial Mutations across Diverse Human Cancers. PLoS Genet. 11(6):e1005333. doi: 10.1371/journal.pgen.1005333. eCollection 2015 Jun.
Posse V, Shahzad S, Falkenberg M, Hällberg BM, Gustafsson CM. (2015) TEFM is a potent stimulator of mitochondrial transcription elongation in vitro. Nucleic Acids Res. 43(5):2615-24. doi: 10.1093/nar/gkv105. Epub 2015 Feb 17.