Cargando…

Replication fork rescue in mammalian mitochondria

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 reg...

Descripción completa

Detalles Bibliográficos
Autores principales: Torregrosa-Muñumer, Rubén, Hangas, Anu, Goffart, Steffi, Blei, Daniel, Zsurka, Gábor, Griffith, Jack, Kunz, Wolfram S., Pohjoismäki, Jaakko L. O.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6584726/
https://www.ncbi.nlm.nih.gov/pubmed/31217442
http://dx.doi.org/10.1038/s41598-019-45244-6
Descripción
Sumario: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.