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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
Resource Relation:
Journal Name: Nature Communications; Journal Volume: 8; Journal Issue: 2017
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},
number = 2017,
volume = 8,
place = {United States},
year = {Wed May 03 00:00:00 EDT 2017},
month = {Wed May 03 00:00:00 EDT 2017}
}
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