Exonuclease of human DNA polymerase gamma disengages its strand displacement function

Qian, He; Shumate, Christie K.; White, Mark A.; Molineux, Ian J.; Yin, Yajiang

doi:10.1016/j.mito.2013.08.003

Cited by 33 publications

(56 citation statements)

References 51 publications

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“…Importantly, Pol γA R 232 is situated in a pocket of the distal Pol γB, forming H‐bonds with H 467 and S 469 , and Pol γA W 235 forms hydrophobic interactions with Pol γB V 338 (Fig C). The replication complex adopts a more compact structure than apo Pol γ in good agreement with solution measurement performed by small‐angle X‐ray scattering (He et al , ). While Pol γA displays several intra‐subunit‐independent structural changes in the fingers, thumb and L‐helix, and the IP subdomains, Pol γB shows no internal structural changes and moves as a rigid body.…”

Section: Resultssupporting

confidence: 84%

Structural basis for processivity and antiviral drug toxicity in human mitochondrial DNA replicase

et al. 2015

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The human DNA polymerase gamma (Pol c) is responsible for DNA replication in mitochondria. Pol c is particularly susceptible to inhibition by dideoxynucleoside-based inhibitors designed to fight viral infection. Here, we report crystal structures of the replicating Pol c-DNA complex bound to either substrate or zalcitabine, an inhibitor used for HIV reverse transcriptase. The structures reveal that zalcitabine binds to the Pol c active site almost identically to the substrate dCTP, providing a structural basis for Pol c-mediated drug toxicity. When compared to the apo form, Pol c undergoes intra-and inter-subunit conformational changes upon formation of the ternary complex with primer/template DNA and substrate. We also find that the accessory subunit Pol cB, which lacks intrinsic enzymatic activity and does not contact the primer/template DNA directly, serves as an allosteric regulator of holoenzyme activities. The structures presented here suggest a mechanism for processivity of the holoenzyme and provide a model for understanding the deleterious effects of Pol c mutations in human disease. Crystal structures of the mitochondrial DNA polymerase, Pol c, in complex with substrate or antiviral inhibitor zalcitabine provide a basis for understanding Pol c-mediated drug toxicity.

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Section: Resultssupporting

confidence: 84%

Structural basis for processivity and antiviral drug toxicity in human mitochondrial DNA replicase

et al. 2015

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“…Importantly, hEXOG enhances Pol γ DNA synthesis by providing an optimal substrate13, therefore increasing the overall efficiency of the mtBER pathway. The Wing domain exerts its effect in several ways.…”

Section: Discussionmentioning

confidence: 99%

A domain in human EXOG converts apoptotic endonuclease to DNA-repair exonuclease

Szymanski

Gmyrek

et al. 2017

Nat Commun

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Human EXOG (hEXOG) is a 5′-exonuclease that is crucial for mitochondrial DNA repair; the enzyme belongs to a nonspecific nuclease family that includes the apoptotic endonuclease EndoG. Here we report biochemical and structural studies of hEXOG, including structures in its apo form and in a complex with DNA at 1.81 and 1.85 Å resolution, respectively. A Wing domain, absent in other ββα-Me members, suppresses endonuclease activity, but confers on hEXOG a strong 5′-dsDNA exonuclease activity that precisely excises a dinucleotide using an intrinsic ‘tape-measure'. The symmetrical apo hEXOG homodimer becomes asymmetrical upon binding to DNA, providing a structural basis for how substrate DNA bound to one active site allosterically regulates the activity of the other. These properties of hEXOG suggest a pathway for mitochondrial BER that provides an optimal substrate for subsequent gap-filling synthesis by DNA polymerase γ.

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“…and embryonic lethality in mice (129,130). When POLγ encounters a 5 end at the termination of DNA replication, the polymerase starts to idle, that is, POLγ initiates successive cycles of polymerization and 3 to 5 exonuclease degradation at the nick (95,131). The idling activity is required for proper ligation because POLγ lacking exonuclease activity will continue DNA synthesis into dsDNA, thereby creating a 5 flap that cannot be used as a substrate for DNA ligase III (95).…”

Section: Initiation Of Mtdna Replication At O Hmentioning

confidence: 99%

Maintenance and Expression of Mammalian Mitochondrial DNA

Gustafsson

Falkenberg

Larsson

2016

Annu. Rev. Biochem.

565

509

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Mammalian mitochondrial DNA (mtDNA) encodes 13 proteins that are essential for the function of the oxidative phosphorylation system, which is composed of four respiratory-chain complexes and adenosine triphosphate (ATP) synthase. Remarkably, the maintenance and expression of mtDNA depend on the mitochondrial import of hundreds of nuclear-encoded proteins that control genome maintenance, replication, transcription, RNA maturation, and mitochondrial translation. The importance of this complex regulatory system is underscored by the identification of numerous mutations of nuclear genes that impair mtDNA maintenance and expression at different levels, causing human mitochondrial diseases with pleiotropic clinical manifestations. The basic scientific understanding of the mechanisms controlling mtDNA function has progressed considerably during the past few years, thanks to advances in biochemistry, genetics, and structural biology. The challenges for the future will be to understand how mtDNA maintenance and expression are regulated and to what extent direct intramitochondrial cross talk between different processes, such as transcription and translation, is important.

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Exonuclease of human DNA polymerase gamma disengages its strand displacement function

Cited by 33 publications

References 51 publications

Structural basis for processivity and antiviral drug toxicity in human mitochondrial DNA replicase

Structural basis for processivity and antiviral drug toxicity in human mitochondrial DNA replicase

A domain in human EXOG converts apoptotic endonuclease to DNA-repair exonuclease

Maintenance and Expression of Mammalian Mitochondrial DNA

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