Replication fork rescue in mammalian mitochondria.

Autor: Torregrosa-Muñumer R; Department of Environmental and Biological Sciences, University of Eastern Finland, P.O. Box 111, 80101, Joensuu, Finland.; Research Programs Unit, Molecular Neurology, University of Helsinki, Helsinki, Finland., Hangas A; Department of Environmental and Biological Sciences, University of Eastern Finland, P.O. Box 111, 80101, Joensuu, Finland., Goffart S; Department of Environmental and Biological Sciences, University of Eastern Finland, P.O. Box 111, 80101, Joensuu, Finland., Blei D; Department of Experimental Epileptology and Cognition Research, University of Bonn, Sigmund-Freud-Str. 25, Bonn, D-53105, Germany., Zsurka G; Department of Experimental Epileptology and Cognition Research, University of Bonn, Sigmund-Freud-Str. 25, Bonn, D-53105, Germany., Griffith J; Lineberger Comprehensive Cancer Center, University of North Carolina at, Chapel Hill, USA., Kunz WS; Department of Experimental Epileptology and Cognition Research, University of Bonn, Sigmund-Freud-Str. 25, Bonn, D-53105, Germany., Pohjoismäki JLO; Department of Environmental and Biological Sciences, University of Eastern Finland, P.O. Box 111, 80101, Joensuu, Finland. Jaakko.Pohjoismaki@uef.fi.
Jazyk: angličtina
Zdroj: Scientific reports [Sci Rep] 2019 Jun 19; Vol. 9 (1), pp. 8785. Date of Electronic Publication: 2019 Jun 19.
DOI: 10.1038/s41598-019-45244-6
Abstrakt: Replication stalling has been associated with the formation of pathological mitochondrial DNA (mtDNA) rearrangements. Yet, almost nothing is known about the fate of stalled replication intermediates in mitochondria. We show here that replication stalling in mitochondria leads to replication fork regression and mtDNA double-strand breaks. The resulting mtDNA fragments are normally degraded by a mechanism involving the mitochondrial exonuclease MGME1, and the loss of this enzyme results in accumulation of linear and recombining mtDNA species. Additionally, replication stress promotes the initiation of alternative replication origins as an apparent means of rescue by fork convergence. Besides demonstrating an interplay between two major mechanisms rescuing stalled replication forks - mtDNA degradation and homology-dependent repair - our data provide evidence that mitochondria employ similar mechanisms to cope with replication stress as known from other genetic systems.
Databáze: MEDLINE
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