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Absence of both MGME1 and POLG EXO abolishes mtDNA whereas absence of either creates unique mtDNA duplications. | LitMetric

AI Article Synopsis

  • - Both POLG and MGME1 are essential for maintaining mitochondrial DNA (mtDNA) in animal cells, with POLG primarily responsible for DNA replication and MGME1 aiding in producing usable DNA ends for ligation.
  • - Research using digital PCR indicates that tissues lacking MGME1 show more fragmented mtDNA than POLG-deficient or normal tissues, with unique duplications identified in Mgme1 knockout hearts, particularly around the D-loop region.
  • - The study suggests that both POLG and MGME1 must function together for effective mtDNA maintenance, revealing that while they can partially compensate for each other, at least one is necessary to prevent genomic abnormalities during DNA replication and repair.

Article Abstract

Both POLG and MGME1 are needed for mitochondrial DNA (mtDNA) maintenance in animal cells. POLG, the primary replicative polymerase of the mitochondria, has an exonuclease activity (3'→5') that corrects for the misincorporation of bases. MGME1 serves as an exonuclease (5'→3'), producing ligatable DNA ends. Although both have a critical role in mtDNA replication and elimination of linear fragments, these mechanisms are still not fully understood. Using digital PCR to evaluate and compare mtDNA integrity, we show that Mgme1 knock out (Mgme1 KK) tissue mtDNA is more fragmented than POLG exonuclease-deficient "Mutator" (Polg MM) or WT tissue. In addition, next generation sequencing of mutant hearts showed abundant duplications in/nearby the D-loop region and unique 100 bp duplications evenly spaced throughout the genome only in Mgme1 KK hearts. However, despite these unique mtDNA features at steady-state, we observed a similar delay in the degradation of mtDNA after an induced double strand DNA break in both Mgme1 KK and Polg MM models. Lastly, we characterized double mutant (Polg MM/Mgme1 KK) cells and show that mtDNA cannot be maintained without at least one of these enzymatic activities. We propose a model for the generation of these genomic abnormalities which suggests a role for MGME1 outside of nascent mtDNA end ligation. Our results highlight the role of MGME1 in and outside of the D-loop region during replication, support the involvement of MGME1 in dsDNA degradation, and demonstrate that POLG EXO and MGME1 can partially compensate for each other in maintaining mtDNA.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11002302PMC
http://dx.doi.org/10.1016/j.jbc.2024.107128DOI Listing

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