We are studying the mechanisms of mitochondrial DNA replication
in mammalian cells, the involvement of mitochondrial DNA binding
proteins, and links with mitochondrial transcription.
For several decades, mtDNA was believed to replicate by a unique,
strand-asynchronous mechanism which our work has increasingly called
into question. Our current view is that at least two mechanisms of
mtDNA replication occur in parallel, although their relationship to
each other is not fully understood. One is conventional, strand-coupled
DNA replication. The other involves extensive RNA incorporation
on the lagging strand, via an unorthodox mechanism.
We are currently focussing on the roles of the two most widely
studied mtDNA-binding proteins (and their homologues) on replication.
These proteins, originally identified as factors involved in
transcriptional initiation (TFAM) and termination (mTERF), appear
to have multiple roles in mtDNA metabolism.
The work involves a long-term collaboration with the laboratory
of Ian Holt in Cambridge,
as well as Hans
Spelbrink in IMT Tampere, and is funded by the University of Tampere,
the Academy of Finland, Tampere University Hospital Medical Research Fund,
Juselius Foundation and the European Union.
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Selected recent publications:
Yasukawa T, Yang MY,
Jacobs HT, Holt IJ (2005) A
bidirectional origin of replication maps to the
major noncoding region of human mitochondrial DNA. Mol.
Cell 18, 651-662.
Holt IJ, Jacobs HT (2003)
Response: the mitochondrial DNA replication
bubble has not burst. Trends Biochem. Sci.
28, 355-356.
Bowmaker M, Yang MY,
Yasukawa T, Reyes A, Jacobs HT, Huberman JA,
Holt IJ (2003) Mammalian
mitochondrial DNA replicates from an initiation
zone. J. Biol. Chem. 278,
50961-50969.
Yang M, Bowmaker M, Reyes
A, Vergani L, Angeli P, Gringeri E, Jacobs HT,
Holt IJ (2002) Biased
incorporation of ribonucleotides on the mitochondrial
L-strand accounts for apparent strand-asymmetric
DNA replication. Cell 111,
495-505.
Kajander OA, Karhunen
PJ, Holt IJ, Jacobs HT (2001)
Prominent mitochondrial DNA recombination
intermediates in human heart muscle. EMBO Rep.
2, 1007-1012.
Holt IJ, Lorimer HE,
Jacobs HT (2000) Coupled
leading- and lagging-strand synthesis
of mammalian mitochondrial DNA. Cell.
100, 515-524.
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