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

• Published in: Nature communications Vol. 8; no. 1; pp. 14959 - 11
• Main Authors: Szymanski, Michal R., Yu, Wangsheng, Gmyrek, Aleksandra M., White, Mark A., Molineux, Ian J., Lee, J. Ching, Yin, Y. Whitney
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 03.05.2017; Nature Publishing Group; Nature Portfolio
• Subjects: 60 APPLIED LIFE SCIENCES; 631/337/1427/1429; 631/535/1266; 82; Amino Acid Sequence; BASIC BIOLOGICAL SCIENCES; Catalytic Domain; Crystallography, X-Ray; DNA - chemistry; DNA - genetics; DNA - metabolism; DNA Repair; Endodeoxyribonucleases - chemistry; Endodeoxyribonucleases - genetics; Endodeoxyribonucleases - metabolism; Endonucleases - chemistry; Endonucleases - genetics; Endonucleases - metabolism; Enzymes; Humanities and Social Sciences; Humans; Kinetics; Mitochondria - genetics; Mitochondria - metabolism; Mitochondrial DNA; Models, Molecular; multidisciplinary; Nucleic Acid Conformation; Oxidative stress; Protein Domains; Proteins; Science; Science (multidisciplinary); Sequence Homology, Amino Acid; Substrate Specificity; United States > US; Texas
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms14959

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. Human EXOG is crucial for mitochondrial DNA repair. Here the authors present the crystal structures of hEXOG in apo form and as DNA complex and suggest a `tape-measure' activity to generate optimal substrates for mitochondrial base excision repair.