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

<div class='caption-title'>hEXOG exonuclease activity.</div>
<div class='caption-title'>Structure of apo hEXOG.</div>
<div class='caption-title'>Structure of hEXOG–dsDNA complex.</div>
Szymanski MR, Yu W, Gmyrek AM, White MA, Molineux IJ, Lee JC, Yin YW
OpenAccess logo Nat Commun 8 14959 (2017)
Related entries: 5t3v, 5t40, 5t4i

Cited: 16 times
EuropePMC logo PMID: 28466855

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.

Articles - 5t5c mentioned but not cited (3)

  1. A domain in human EXOG converts apoptotic endonuclease to DNA-repair exonuclease. Szymanski MR, Yu W, Gmyrek AM, White MA, Molineux IJ, Lee JC, Yin YW. Nat Commun 8 14959 (2017)
  2. A unique exonuclease ExoG cleaves between RNA and DNA in mitochondrial DNA replication. Wu CC, Lin JLJ, Yang-Yen HF, Yuan HS. Nucleic Acids Res 47 5405-5419 (2019)
  3. Recruiting Mechanism and Functional Role of a Third Metal Ion in the Enzymatic Activity of 5' Structure-Specific Nucleases. Donati E, Genna V, De Vivo M. J Am Chem Soc 142 2823-2834 (2020)


Reviews citing this publication (4)

  1. Mitochondrial Gene Expression and Beyond-Novel Aspects of Cellular Physiology. Kotrys AV, Szczesny RJ. Cells 9 E17 (2019)
  2. Mitonuclear Interactions in the Maintenance of Mitochondrial Integrity. Karakaidos P, Rampias T. Life (Basel) 10 E173 (2020)
  3. The Role of Poly(ADP-ribose) Polymerase 1 in Nuclear and Mitochondrial Base Excision Repair. Herrmann GK, Yin YW. Biomolecules 13 1195 (2023)
  4. Mitochondrial disorders as a mechanism for the development of obese Sarcopenia. Liao T, Xiong L, Wang X, Yang S, Liang Z. Diabetol Metab Syndr 15 224 (2023)

Articles citing this publication (9)

  1. Dinucleotide Degradation by REXO2 Maintains Promoter Specificity in Mammalian Mitochondria. Nicholls TJ, Spåhr H, Jiang S, Siira SJ, Koolmeister C, Sharma S, Kauppila JHK, Jiang M, Kaever V, Rackham O, Chabes A, Falkenberg M, Filipovska A, Larsson NG, Gustafsson CM. Mol Cell 76 784-796.e6 (2019)
  2. Quantitative proteomics revealed C6orf203/MTRES1 as a factor preventing stress-induced transcription deficiency in human mitochondria. Kotrys AV, Cysewski D, Czarnomska SD, Pietras Z, Borowski LS, Dziembowski A, Szczesny RJ. Nucleic Acids Res 47 7502-7517 (2019)
  3. Structural insights into DNA degradation by human mitochondrial nuclease MGME1. Yang C, Wu R, Liu H, Chen Y, Gao Y, Chen X, Li Y, Ma J, Li J, Gan J. Nucleic Acids Res 46 11075-11088 (2018)
  4. Poly(ADP-ribose) polymerase 1 regulates mitochondrial DNA repair in an NAD-dependent manner. Herrmann GK, Russell WK, Garg NJ, Yin YW. J Biol Chem 296 100309 (2021)
  5. Crystal structure of NucB, a biofilm-degrading endonuclease. Baslé A, Hewitt L, Koh A, Lamb HK, Thompson P, Burgess JG, Hall MJ, Hawkins AR, Murray H, Lewis RJ. Nucleic Acids Res 46 473-484 (2018)
  6. Hypothesis: RNA and DNA Viral Sequence Integration into the Mammalian Host Genome Supports Long-Term B Cell and T Cell Adaptive Immunity. Hurwitz JL, Jones BG, Charpentier E, Woodland DL. Viral Immunol 30 628-632 (2017)
  7. Human EXOG Possesses Strong AP Hydrolysis Activity: Implication on Mitochondrial DNA Base Excision Repair. Szymanski MR, Karlowicz A, Herrmann GK, Cen Y, Yin YW. J Am Chem Soc 144 23543-23550 (2022)
  8. In vitro reconstitution reveals a key role of human mitochondrial EXOG in RNA primer processing. Karlowicz A, Dubiel AB, Czerwinska J, Bledea A, Purzycki P, Grzelewska M, McAuley RJ, Szczesny RJ, Brzuska G, Krol E, Szczesny B, Szymanski MR. Nucleic Acids Res 50 7991-8007 (2022)
  9. The 5'-phosphate enhances the DNA-binding and exonuclease activities of human mitochondrial genome maintenance exonuclease 1 (MGME1). Urrutia KM, Xu W, Zhao L. J Biol Chem 298 102306 (2022)


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