Roles of the mitochondrial replisome in mitochondrial DNA deletion formation

Genetics and Molecular Biology
M T OliveiraG L Ciesielski

Abstract

Mitochondrial DNA (mtDNA) deletions are a common cause of human mitochondrial diseases. Mutations in the genes encoding components of the mitochondrial replisome, such as DNA polymerase gamma (Pol γ) and the mtDNA helicase Twinkle, have been associated with the accumulation of such deletions and the development of pathological conditions in humans. Recently, we demonstrated that changes in the level of wild-type Twinkle promote mtDNA deletions, which implies that not only mutations in, but also dysregulation of the stoichiometry between the replisome components is potentially pathogenic. The mechanism(s) by which alterations to the replisome function generate mtDNA deletions is(are) currently under debate. It is commonly accepted that stalling of the replication fork at sites likely to form secondary structures precedes the deletion formation. The secondary structural elements can be bypassed by the replication-slippage mechanism. Otherwise, stalling of the replication fork can generate single- and double-strand breaks, which can be repaired through recombination leading to the elimination of segments between the recombination sites. Here, we discuss aberrances of the replisome in the context of the two debated outcomes, and su...Continue Reading

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Citations

Sep 24, 2020·Aging Clinical and Experimental Research·Allen HerbstJonathan Wanagat
Jul 3, 2021·International Journal of Molecular Sciences·Javier RamónRamon Martí

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Methods Mentioned

BETA
enzymatic cleavage
electrophoresis
fluorescence microscopy

Software Mentioned

Twinkle

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