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The exonuclease activity of DNA polymerase gamma is required for ligation during mitochondrial DNA replication

Journal article
Authors Bertil Macao
Jay Uhler
Triinu Siibak
Xuefeng Zhu
Yonghong Shi
Wenwen Sheng
Monica Olsson
J. B. Stewart
Claes M Gustafsson
Maria Falkenberg
Published in Nature Communications
Volume 6
Pages article no. 7303
ISSN 2041-1723
Publication year 2015
Published at Institute of Biomedicine, Department of Medical Biochemistry and Cell Biology
Pages article no. 7303
Language en
Links dx.doi.org/10.1038/ncomms8303
Keywords STRAND DISPLACEMENT ACTIVITY, OKAZAKI FRAGMENT MATURATION, SUBSTANTIA-NIGRA NEURONS, FLAP ENDONUCLEASE-1, LIGATABLE NICK, LIGASE-III, MUTATIONS, DELTA, MAINTENANCE, DELETIONS
Subject categories Cell Biology, Cell and molecular biology

Abstract

Mitochondrial DNA (mtDNA) polymerase gamma (POL gamma) harbours a 3'-5' exonuclease proofreading activity. Here we demonstrate that this activity is required for the creation of ligatable ends during mtDNA replication. Exonuclease-deficient POL gamma fails to pause on reaching a downstream 5'-end. Instead, the enzyme continues to polymerize into double-stranded DNA, creating an unligatable 5'-flap. Disease-associated mutations can both increase and decrease exonuclease activity and consequently impair DNA ligation. In mice, inactivation of the exonuclease activity causes an increase in mtDNA mutations and premature ageing phenotypes. These mutator mice also contain high levels of truncated, linear fragments of mtDNA. We demonstrate that the formation of these fragments is due to impaired ligation, causing nicks near the origin of heavy-strand DNA replication. In the subsequent round of replication, the nicks lead to double-strand breaks and linear fragment formation.

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http://gu.se/english/research/publication/?publicationId=220250
Utskriftsdatum: 2019-08-17