EXOG, a Novel Paralog of Endonuclease G in Higher Eukaryotes

Overview

Journal Nucleic Acids Res

Publisher Oxford University Press

Specialty Biochemistry

Date 2008 Jan 12

PMID 18187503

Citations 44

Authors

Iwona A Cymerman

Inn Chung

Benedikt M Beckmann

Janusz M Bujnicki

Gregor Meiss

Affiliations

Soon will be listed here.

Abstract

Evolutionary conserved mitochondrial nucleases are involved in programmed cell death and normal cell proliferation in lower and higher eukaryotes. The endo/exonuclease Nuc1p, also termed 'yeast Endonuclease G (EndoG)', is a member of this class of enzymes that differs from mammalian homologs by the presence of a 5'-3' exonuclease activity in addition to its broad spectrum endonuclease activity. However, this exonuclease activity is thought to be essential for a function of the yeast enzyme in DNA recombination and repair. Here we show that higher eukaryotes in addition to EndoG contain its paralog 'EXOG', a novel EndoG-like mitochondrial endo/exonuclease. We find that during metazoan evolution duplication of an ancestral nuclease gene obviously generated the paralogous EndoG- and EXOG-protein subfamilies in higher eukaryotes, thereby maintaining the full endo/exonuclease activity found in mitochondria of lower eukaryotes. We demonstrate that human EXOG is a dimeric mitochondrial enzyme that displays 5'-3' exonuclease activity and further differs from EndoG in substrate specificity. We hypothesize that in higher eukaryotes the complementary enzymatic activities of EndoG and EXOG probably together account for both, the lethal and vital functions of conserved mitochondrial endo/exonucleases.

Citing Articles

Mitochondrial exonuclease EXOG supports DNA integrity by the removal of single-stranded DNA flaps.

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Endonuclease G promotes hepatic mitochondrial respiration by selectively increasing mitochondrial tRNA production.

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Single-Nucleotide Polymorphisms in Genes Maintaining the Stability of Mitochondrial DNA Affect the Occurrence, Onset, Severity and Treatment of Major Depressive Disorder.

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Maintenance of Flap Endonucleases for Long-Patch Base Excision DNA Repair in Mouse Muscle and Neuronal Cells Differentiated In Vitro.

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The Role of Poly(ADP-ribose) Polymerase 1 in Nuclear and Mitochondrial Base Excision Repair.

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References

Huang K, Ku C, Lehman I . Endonuclease G: a role for the enzyme in recombination and cellular proliferation. Proc Natl Acad Sci U S A. 2006; 103(24):8995-9000. PMC: 1482554. DOI: 10.1073/pnas.0603445103. View

Kurowski M, Bujnicki J . GeneSilico protein structure prediction meta-server. Nucleic Acids Res. 2003; 31(13):3305-7. PMC: 168964. DOI: 10.1093/nar/gkg557. View

Widlak P, Li L, Wang X, Garrard W . Action of recombinant human apoptotic endonuclease G on naked DNA and chromatin substrates: cooperation with exonuclease and DNase I. J Biol Chem. 2001; 276(51):48404-9. DOI: 10.1074/jbc.M108461200. View

Irvine R, Adachi N, Shibata D, Cassell G, Yu K, Karanjawala Z . Generation and characterization of endonuclease G null mice. Mol Cell Biol. 2004; 25(1):294-302. PMC: 538798. DOI: 10.1128/MCB.25.1.294-302.2005. View

Dake E, Hofmann T, McIntire S, Hudson A, Zassenhaus H . Purification and properties of the major nuclease from mitochondria of Saccharomyces cerevisiae. J Biol Chem. 1988; 263(16):7691-702. View

Lunin V, Levdikov V, Shlyapnikov S, Blagova E, Lunin V, Wilson K . Three-dimensional structure of Serratia marcescens nuclease at 1.7 A resolution and mechanism of its action. FEBS Lett. 1997; 412(1):217-22. DOI: 10.1016/s0014-5793(97)00512-7. View

Friedhoff P, Franke I, Meiss G, Wende W, Krause K, Pingoud A . A similar active site for non-specific and specific endonucleases. Nat Struct Biol. 1999; 6(2):112-3. DOI: 10.1038/5796. View

Arnoult D, Gaume B, Karbowski M, Sharpe J, Cecconi F, Youle R . Mitochondrial release of AIF and EndoG requires caspase activation downstream of Bax/Bak-mediated permeabilization. EMBO J. 2003; 22(17):4385-99. PMC: 202365. DOI: 10.1093/emboj/cdg423. View

Whelan S, Goldman N . A general empirical model of protein evolution derived from multiple protein families using a maximum-likelihood approach. Mol Biol Evol. 2001; 18(5):691-9. DOI: 10.1093/oxfordjournals.molbev.a003851. View

10.

Davies A, Hershman S, Stabley G, Hoek J, Peterson J, Cahill A . A Ca2+-induced mitochondrial permeability transition causes complete release of rat liver endonuclease G activity from its exclusive location within the mitochondrial intermembrane space. Identification of a novel endo-exonuclease activity residing.... Nucleic Acids Res. 2003; 31(4):1364-73. PMC: 150224. DOI: 10.1093/nar/gkg205. View

11.

Buttner S, Eisenberg T, Carmona-Gutierrez D, Ruli D, Knauer H, Ruckenstuhl C . Endonuclease G regulates budding yeast life and death. Mol Cell. 2007; 25(2):233-46. DOI: 10.1016/j.molcel.2006.12.021. View

12.

Guindon S, Lethiec F, Duroux P, Gascuel O . PHYML Online--a web server for fast maximum likelihood-based phylogenetic inference. Nucleic Acids Res. 2005; 33(Web Server issue):W557-9. PMC: 1160113. DOI: 10.1093/nar/gki352. View

13.

Renaud J . Endonuclease G: a (dG)n X (dC)n-specific DNase from higher eukaryotes. EMBO J. 1987; 6(2):401-7. PMC: 553410. DOI: 10.1002/j.1460-2075.1987.tb04769.x. View

14.

Kabsch W, Sander C . Dictionary of protein secondary structure: pattern recognition of hydrogen-bonded and geometrical features. Biopolymers. 1983; 22(12):2577-637. DOI: 10.1002/bip.360221211. View

15.

Cote J, Renaud J . Recognition of (dG)n.(dC)n sequences by endonuclease G. Characterization of the calf thymus nuclease. J Biol Chem. 1989; 264(6):3301-10. View

16.

Parrish J, Li L, Klotz K, Ledwich D, Wang X, Xue D . Mitochondrial endonuclease G is important for apoptosis in C. elegans. Nature. 2001; 412(6842):90-4. DOI: 10.1038/35083608. View

17.

Schaffer A, Aravind L, Madden T, Shavirin S, Spouge J, Wolf Y . Improving the accuracy of PSI-BLAST protein database searches with composition-based statistics and other refinements. Nucleic Acids Res. 2001; 29(14):2994-3005. PMC: 55814. DOI: 10.1093/nar/29.14.2994. View

18.

Burhans W, Weinberger M . Yeast endonuclease G: complex matters of death, and of life. Mol Cell. 2007; 25(3):323-5. DOI: 10.1016/j.molcel.2007.01.030. View

19.

Widlak P, Garrard W . Discovery, regulation, and action of the major apoptotic nucleases DFF40/CAD and endonuclease G. J Cell Biochem. 2005; 94(6):1078-87. DOI: 10.1002/jcb.20409. View

20.

Cote J . Primers for mitochondrial DNA replication generated by endonuclease G. Science. 1993; 261(5122):765-9. DOI: 10.1126/science.7688144. View