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Mitochondrial tyrosyl‐ DNA phosphodiesterase 2 and its TDP 2 S short isoform
Author(s) -
Huang Sharyin N,
Dalla Rosa Ilaria,
Michaels Stephanie A,
Tulumello David V,
Agama Keli,
Khiati Salim,
Jean Sae Rin,
Baechler Simone A,
Factor Valentina M,
Varma Sudhir,
Murai Junko,
Miller Jenkins Lisa M,
Kelley Shana O,
Pommier Yves
Publication year - 2018
Publication title -
embo reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.584
H-Index - 184
eISSN - 1469-3178
pISSN - 1469-221X
DOI - 10.15252/embr.201642139
Subject(s) - cancer , library science , medicine , computer science
Tyrosyl‐ DNA phosphodiesterase 2 ( TDP 2) repairs abortive topoisomerase II cleavage complexes. Here, we identify a novel short isoform of TDP 2 ( TDP 2 S ) expressed from an alternative transcription start site. TDP 2 S contains a mitochondrial targeting sequence, contributing to its enrichment in the mitochondria and cytosol, while full‐length TDP 2 contains a nuclear localization signal and the ubiquitin‐associated domain in the N‐terminus. Our study reveals that both TDP 2 isoforms are present and active in the mitochondria. Comparison of isogenic wild‐type ( WT ) and TDP 2 knockout ( TDP 2 −/−/− ) DT 40 cells shows that TDP 2 −/−/− cells are hypersensitive to mitochondrial‐targeted doxorubicin (mtDox), and that complementing TDP 2 −/−/− cells with human TDP 2 restores resistance to mtDox. Furthermore, mtDox selectively depletes mitochondrial DNA in TDP 2 −/−/− cells. Using CRISPR ‐engineered human cells expressing only the TDP 2 S isoform, we show that TDP 2 S also protects human cells against mtDox. Finally, lack of TDP 2 in the mitochondria reduces the mitochondria transcription levels in two different human cell lines. In addition to identifying a novel TDP 2 S isoform, our report demonstrates the presence and importance of both TDP 2 isoforms in the mitochondria.