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

Abstract

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.

Authors:
; ; ; ORCiD logo; ; ;
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
NIHOTHER
OSTI Identifier:
1400284
Resource Type:
Journal Article
Journal Name:
Nature Communications
Additional Journal Information:
Journal Volume: 8; Journal Issue: 2017; Journal ID: ISSN 2041-1723
Publisher:
Nature Publishing Group
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES

Citation Formats

Szymanski, Michal R., Yu, Wangsheng, Gmyrek, Aleksandra M., White, Mark A., Molineux, Ian J., Lee, J. Ching, and Yin, Y. Whitney. A domain in human EXOG converts apoptotic endonuclease to DNA-repair exonuclease. United States: N. p., 2017. Web. doi:10.1038/ncomms14959.
Szymanski, Michal R., Yu, Wangsheng, Gmyrek, Aleksandra M., White, Mark A., Molineux, Ian J., Lee, J. Ching, & Yin, Y. Whitney. A domain in human EXOG converts apoptotic endonuclease to DNA-repair exonuclease. United States. doi:10.1038/ncomms14959.
Szymanski, Michal R., Yu, Wangsheng, Gmyrek, Aleksandra M., White, Mark A., Molineux, Ian J., Lee, J. Ching, and Yin, Y. Whitney. Wed . "A domain in human EXOG converts apoptotic endonuclease to DNA-repair exonuclease". United States. doi:10.1038/ncomms14959.
@article{osti_1400284,
title = {A domain in human EXOG converts apoptotic endonuclease to DNA-repair exonuclease},
author = {Szymanski, Michal R. and Yu, Wangsheng and Gmyrek, Aleksandra M. and White, Mark A. and Molineux, Ian J. and Lee, J. Ching and Yin, Y. Whitney},
abstractNote = {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.},
doi = {10.1038/ncomms14959},
journal = {Nature Communications},
issn = {2041-1723},
number = 2017,
volume = 8,
place = {United States},
year = {2017},
month = {5}
}

Works referenced in this record:

Base Excision Repair
journal, April 2013


Flap Endonuclease 1
journal, June 2013


MolProbity : all-atom structure validation for macromolecular crystallography
journal, December 2009

  • Chen, Vincent B.; Arendall, W. Bryan; Headd, Jeffrey J.
  • Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 1
  • DOI: 10.1107/S0907444909042073

Features and development of Coot
journal, March 2010

  • Emsley, P.; Lohkamp, B.; Scott, W. G.
  • Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 4
  • DOI: 10.1107/S0907444910007493

New developments in the ATSAS program package for small-angle scattering data analysis
journal, March 2012

  • Petoukhov, Maxim V.; Franke, Daniel; Shkumatov, Alexander V.
  • Journal of Applied Crystallography, Vol. 45, Issue 2
  • DOI: 10.1107/S0021889812007662

The Escherichia coli PriA Helicase Specifically Recognizes Gapped DNA Substrates : EFFECT OF THE TWO NUCLEOTIDE-BINDING SITES OF THE ENZYME ON THE RECOGNITION PROCESS
journal, January 2010

  • Szymanski, Michal R.; Jezewska, Maria J.; Bujalowski, Wlodzimierz
  • Journal of Biological Chemistry, Vol. 285, Issue 13
  • DOI: 10.1074/jbc.M109.094789

Nucleases: diversity of structure, function and mechanism
journal, September 2010


PHENIX: a comprehensive Python-based system for macromolecular structure solution
journal, January 2010

  • Adams, Paul D.; Afonine, Pavel V.; Bunkóczi, Gábor
  • Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 2, p. 213-221
  • DOI: 10.1107/S0907444909052925

SEDPHAT – A platform for global ITC analysis and global multi-method analysis of molecular interactions
journal, April 2015


The cutting edges in DNA repair, licensing, and fidelity: DNA and RNA repair nucleases sculpt DNA to measure twice, cut once
journal, July 2014


Phaser crystallographic software
journal, July 2007

  • McCoy, Airlie J.; Grosse-Kunstleve, Ralf W.; Adams, Paul D.
  • Journal of Applied Crystallography, Vol. 40, Issue 4
  • DOI: 10.1107/S0021889807021206