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MGME1 processes flaps into ligatable nicks in concert with DNA polymerase gamma during mtDNA replication

Journal article
Authors Jay Uhler
Christian Thörn
Thomas J. Nicholls
S. Matic
D. Milenkovic
Claes M Gustafsson
Maria Falkenberg
Published in Nucleic Acids Research
Volume 44
Issue 12
Pages 5861-5871
ISSN 0305-1048
Publication year 2016
Published at Institute of Biomedicine
Pages 5861-5871
Language en
Links dx.doi.org/10.1093/nar/gkw468
Keywords human mitochondrial-dna, okazaki fragment maturation, base, excision-repair, transfer-rna synthetases, accessory subunit, ligase, iii, exonuclease, disease, endonuclease, mice, Biochemistry & Molecular Biology
Subject categories Clinical Medicine

Abstract

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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