Journal
NUCLEIC ACIDS RESEARCH
Volume 44, Issue 12, Pages 5861-5871Publisher
OXFORD UNIV PRESS
DOI: 10.1093/nar/gkw468
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Funding
- Swedish Research Council grants [2013-3621, 2012-2583]
- Swedish Cancer Foundation
- European Research Council [261248, 268897]
- Wallenbergs foundation
- Wilhelm and Martina Lundgrens foundation
- ERC
- European Research Council (ERC) [268897, 261248] Funding Source: European Research Council (ERC)
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Recently, MGME1 was identified as a mitochondrial DNA nuclease with preference for single-stranded DNA (ssDNA) substrates. Loss-of-function mutations in patients lead to mitochondrial disease with DNA depletion, deletions, duplications and rearrangements. Here, we assess the biochemical role of MGME1 in the processing of flap intermediates during mitochondrial DNA replication using reconstituted systems. We show that MGME1 can cleave flaps to enable efficient ligation of newly replicated DNA strands in combination with POL gamma. MGME1 generates a pool of imprecisely cut products (short flaps, nicks and gaps) that are converted to ligatable nicks by POL gamma through extension or excision of the 3'-end strand. This is dependent on the 3'-5' exonuclease activity of POL gamma which limits strand displacement activity and enables POL gamma to back up to the nick by 3'-5' degradation. We also demonstrate that POL gamma-driven strand displacement is sufficient to generate DNA- but not RNA-flap substrates suitable for MGME1 cleavage and ligation during replication. Our findings have implications for RNA primer removal models, the 5'-end processing of nascent DNA at OriH, and DNA repair.
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