Unleashing a novel function of Endonuclease G in mitochondrial genome instability
Having its genome makes the mitochondrion a unique and semiautonomous organelle within cells. Mammalian mitochondrial DNA (mtDNA) is a double-stranded closed circular molecule of about 16 kb coding for 37 genes. Mutations, including deletions in the mitochondrial genome, can culminate in different h...
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
eLife Sciences Publications Ltd
2022-11-01
|
| Series: | eLife |
| Subjects: | |
| Online Access: | https://elifesciences.org/articles/69916 |
| _version_ | 1798015913950183424 |
|---|---|
| author | Sumedha Dahal Humaira Siddiqua Shivangi Sharma Ravi K Babu Diksha Rathore Sheetal Sharma Sathees C Raghavan |
| author_facet | Sumedha Dahal Humaira Siddiqua Shivangi Sharma Ravi K Babu Diksha Rathore Sheetal Sharma Sathees C Raghavan |
| author_sort | Sumedha Dahal |
| collection | DOAJ |
| description | Having its genome makes the mitochondrion a unique and semiautonomous organelle within cells. Mammalian mitochondrial DNA (mtDNA) is a double-stranded closed circular molecule of about 16 kb coding for 37 genes. Mutations, including deletions in the mitochondrial genome, can culminate in different human diseases. Mapping the deletion junctions suggests that the breakpoints are generally seen at hotspots. ‘9 bp deletion’ (8271–8281), seen in the intergenic region of cytochrome c oxidase II/tRNALys, is the most common mitochondrial deletion. While it is associated with several diseases like myopathy, dystonia, and hepatocellular carcinoma, it has also been used as an evolutionary marker. However, the mechanism responsible for its fragility is unclear. In the current study, we show that Endonuclease G, a mitochondrial nuclease responsible for nonspecific cleavage of nuclear DNA during apoptosis, can induce breaks at sequences associated with ‘9 bp deletion’ when it is present on a plasmid or in the mitochondrial genome. Through a series of in vitro and intracellular studies, we show that Endonuclease G binds to G-quadruplex structures formed at the hotspot and induces DNA breaks. Therefore, we uncover a new role for Endonuclease G in generating mtDNA deletions, which depends on the formation of G4 DNA within the mitochondrial genome. In summary, we identify a novel property of Endonuclease G, besides its role in apoptosis and the recently described ‘elimination of paternal mitochondria during fertilisation. |
| first_indexed | 2024-04-11T15:42:22Z |
| format | Article |
| id | doaj.art-34967d62b3fd4f759abfee56bf506b59 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-11T15:42:22Z |
| publishDate | 2022-11-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-34967d62b3fd4f759abfee56bf506b592022-12-22T04:15:44ZengeLife Sciences Publications LtdeLife2050-084X2022-11-011110.7554/eLife.69916Unleashing a novel function of Endonuclease G in mitochondrial genome instabilitySumedha Dahal0https://orcid.org/0000-0003-3682-5656Humaira Siddiqua1Shivangi Sharma2Ravi K Babu3Diksha Rathore4Sheetal Sharma5Sathees C Raghavan6https://orcid.org/0000-0003-3003-1417Department of Biochemistry, Indian Institute of Science Bangalore, Bangalore, IndiaDepartment of Biochemistry, Indian Institute of Science Bangalore, Bangalore, IndiaDepartment of Biochemistry, Indian Institute of Science Bangalore, Bangalore, IndiaDepartment of Biochemistry, Indian Institute of Science Bangalore, Bangalore, IndiaDepartment of Biochemistry, Indian Institute of Science Bangalore, Bangalore, IndiaDepartment of Experimental Medicine and Biotechnology, Post Graduate Institute of Medical Education and Research, Chandigarh, IndiaDepartment of Biochemistry, Indian Institute of Science Bangalore, Bangalore, IndiaHaving its genome makes the mitochondrion a unique and semiautonomous organelle within cells. Mammalian mitochondrial DNA (mtDNA) is a double-stranded closed circular molecule of about 16 kb coding for 37 genes. Mutations, including deletions in the mitochondrial genome, can culminate in different human diseases. Mapping the deletion junctions suggests that the breakpoints are generally seen at hotspots. ‘9 bp deletion’ (8271–8281), seen in the intergenic region of cytochrome c oxidase II/tRNALys, is the most common mitochondrial deletion. While it is associated with several diseases like myopathy, dystonia, and hepatocellular carcinoma, it has also been used as an evolutionary marker. However, the mechanism responsible for its fragility is unclear. In the current study, we show that Endonuclease G, a mitochondrial nuclease responsible for nonspecific cleavage of nuclear DNA during apoptosis, can induce breaks at sequences associated with ‘9 bp deletion’ when it is present on a plasmid or in the mitochondrial genome. Through a series of in vitro and intracellular studies, we show that Endonuclease G binds to G-quadruplex structures formed at the hotspot and induces DNA breaks. Therefore, we uncover a new role for Endonuclease G in generating mtDNA deletions, which depends on the formation of G4 DNA within the mitochondrial genome. In summary, we identify a novel property of Endonuclease G, besides its role in apoptosis and the recently described ‘elimination of paternal mitochondria during fertilisation.https://elifesciences.org/articles/69916tetraplexesmitochondrial fragilityEndo Gdouble-strand breaksMMEJmitochondrial deletion |
| spellingShingle | Sumedha Dahal Humaira Siddiqua Shivangi Sharma Ravi K Babu Diksha Rathore Sheetal Sharma Sathees C Raghavan Unleashing a novel function of Endonuclease G in mitochondrial genome instability eLife tetraplexes mitochondrial fragility Endo G double-strand breaks MMEJ mitochondrial deletion |
| title | Unleashing a novel function of Endonuclease G in mitochondrial genome instability |
| title_full | Unleashing a novel function of Endonuclease G in mitochondrial genome instability |
| title_fullStr | Unleashing a novel function of Endonuclease G in mitochondrial genome instability |
| title_full_unstemmed | Unleashing a novel function of Endonuclease G in mitochondrial genome instability |
| title_short | Unleashing a novel function of Endonuclease G in mitochondrial genome instability |
| title_sort | unleashing a novel function of endonuclease g in mitochondrial genome instability |
| topic | tetraplexes mitochondrial fragility Endo G double-strand breaks MMEJ mitochondrial deletion |
| url | https://elifesciences.org/articles/69916 |
| work_keys_str_mv | AT sumedhadahal unleashinganovelfunctionofendonucleaseginmitochondrialgenomeinstability AT humairasiddiqua unleashinganovelfunctionofendonucleaseginmitochondrialgenomeinstability AT shivangisharma unleashinganovelfunctionofendonucleaseginmitochondrialgenomeinstability AT ravikbabu unleashinganovelfunctionofendonucleaseginmitochondrialgenomeinstability AT diksharathore unleashinganovelfunctionofendonucleaseginmitochondrialgenomeinstability AT sheetalsharma unleashinganovelfunctionofendonucleaseginmitochondrialgenomeinstability AT satheescraghavan unleashinganovelfunctionofendonucleaseginmitochondrialgenomeinstability |