Role of tyrosyl-DNA phosphodiesterase (TDP1) in mitochondria.
Human tyrosyl-DNA phosphodiesterase (TDP1) hydrolyzes the phosphodiester bond at a DNA 3'-end linked to a tyrosyl moiety and has been implicated in the repair of topoisomerase I (Top1)-DNA covalent complexes. TDP1 can also hydrolyze other 3'-end DNA alterations including 3'-phosphoglycolate and 3'-abasic sites, and exhibits 3'-nucleosidase activity indicating it may function as a general 3'-end-processing DNA repair enzyme. Here, using laser confocal microscopy, subcellular fractionation and biochemical analyses we demonstrate that a fraction of the TDP1 encoded by the nuclear TDP1 gene localizes to mitochondria. We also show that mitochondrial base excision repair depends on TDP1 activity and provide evidence that TDP1 is required for efficient repair of oxidative damage in mitochondrial DNA. Together, our findings provide evidence for TDP1 as a novel mitochondrial enzyme.
Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-4255, USA.
Benu Brata
BB
Das
Thomas S
TS
Dexheimer
Kasthuraiah
K
Maddali
Yves
Y
Pommier
D000818:Animals; D001483:Base Sequence; D002457:Cell Extracts; D045744:Cell Line, Tumor; D004249:DNA Damage; D000072481:DNA Ligase ATP; D011088:DNA Ligases / Q000378:metabolism; D004260:DNA Repair; D004272:DNA, Mitochondrial / Q000378:metabolism; D006801:Humans; D051379:Mice; D008928:Mitochondria / Q000201:enzymology*; D008969:Molecular Sequence Data; D018384:Oxidative Stress; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism*; D000075223:Poly-ADP-Ribose Binding Proteins; D021381:Protein Transport; D029867:Xenopus Proteins
D002457:Cell Extracts; D004272:DNA, Mitochondrial; D000075223:Poly-ADP-Ribose Binding Proteins; D029867:Xenopus Proteins; D010727:Phosphoric Diester Hydrolases; C498508:TDP1 protein, human; C524959:Tdp1 protein, mouse; D011088:DNA Ligases; D000072481:DNA Ligase ATP; C000618816:DNA ligase III alpha protein, Xenopus