Mitochondrial tyrosyl‐ DNA phosphodiesterase 2 and its TDP 2 S short isoform
| Autor: | Ilaria Dalla Rosa, Stephanie A. Michaels, Keli Agama, Simone A Baechler, Lisa M. Miller Jenkins, Salim Khiati, Valentina M. Factor, Yves Pommier, Shar-yin N. Huang, Sae Rin Jean, David V. Tulumello, Sudhir Varma, Junko Murai, Shana O. Kelley |
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| Přispěvatelé: | Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS) |
| Rok vydání: | 2018 |
| Předmět: |
Enzymologic
0301 basic medicine Gene isoform Mitochondrial DNA DNA repair Drug Resistance Mitochondrion Biochemistry Cell Line Gene Knockout Techniques 03 medical and health sciences Transcription (biology) Neoplasms Genetics Protein Isoforms Humans Molecular Biology Tumor biology Chemistry Topoisomerase Nuclear Proteins Cell biology mitochondria Alternative Splicing Cytosol 030104 developmental biology Gene Expression Regulation Doxorubicin biology.protein Neoplasm [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology Nuclear localization sequence Transcription Factors |
| Zdroj: | EMBO Reports EMBO Reports, EMBO Press, 2018, 19 (3), pp.e42139. ⟨10.15252/embr.201642139⟩ |
| ISSN: | 1469-3178 1469-221X |
| DOI: | 10.15252/embr.201642139 |
| Popis: | Tyrosyl-DNA phosphodiesterase 2 (TDP2) repairs abortive topoisomerase II cleavage complexes. Here, we identify a novel short isoform of TDP2 (TDP2S) expressed from an alternative transcription start site. TDP2S contains a mitochondrial targeting sequence, contributing to its enrichment in the mitochondria and cytosol, while full-length TDP2 contains a nuclear localization signal and the ubiquitin-associated domain in the N-terminus. Our study reveals that both TDP2 isoforms are present and active in the mitochondria. Comparison of isogenic wild-type (WT) and TDP2 knockout (TDP2-/-/-) DT40 cells shows that TDP2-/-/- cells are hypersensitive to mitochondrial-targeted doxorubicin (mtDox), and that complementing TDP2-/-/- cells with human TDP2 restores resistance to mtDox. Furthermore, mtDox selectively depletes mitochondrial DNA in TDP2-/-/- cells. Using CRISPR-engineered human cells expressing only the TDP2S isoform, we show that TDP2S also protects human cells against mtDox. Finally, lack of TDP2 in the mitochondria reduces the mitochondria transcription levels in two different human cell lines. In addition to identifying a novel TDP2S isoform, our report demonstrates the presence and importance of both TDP2 isoforms in the mitochondria. |
| Databáze: | OpenAIRE |
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