Aprataxin localizes to mitochondria and preserves mitochondrial function
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Aprataxin localizes to mitochondria and preserves mitochondrial function. / Sykora, Peter; Croteau, Deborah L; Bohr, Vilhelm A; Wilson, David M.
In: Proceedings of the National Academy of Sciences USA (PNAS), Vol. 108, No. 18, 03.05.2011, p. 7437-42.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Aprataxin localizes to mitochondria and preserves mitochondrial function
AU - Sykora, Peter
AU - Croteau, Deborah L
AU - Bohr, Vilhelm A
AU - Wilson, David M
PY - 2011/5/3
Y1 - 2011/5/3
N2 - Ataxia with oculomotor apraxia 1 is caused by mutation in the APTX gene, which encodes the DNA strand-break repair protein aprataxin. Aprataxin exhibits homology to the histidine triad superfamily of nucleotide hydrolases and transferases and removes 5'-adenylate groups from DNA that arise from aborted ligation reactions. We report herein that aprataxin localizes to mitochondria in human cells and we identify an N-terminal amino acid sequence that targets certain isoforms of the protein to this intracellular compartment. We also show that transcripts encoding this unique N-terminal stretch are expressed in the human brain, with highest production in the cerebellum. Depletion of aprataxin in human SH-SY5Y neuroblastoma cells and primary skeletal muscle myoblasts results in mitochondrial dysfunction, which is revealed by reduced citrate synthase activity and mtDNA copy number. Moreover, mtDNA, not nuclear DNA, was found to have higher levels of background DNA damage on aprataxin knockdown, suggesting a direct role for the enzyme in mtDNA processing.
AB - Ataxia with oculomotor apraxia 1 is caused by mutation in the APTX gene, which encodes the DNA strand-break repair protein aprataxin. Aprataxin exhibits homology to the histidine triad superfamily of nucleotide hydrolases and transferases and removes 5'-adenylate groups from DNA that arise from aborted ligation reactions. We report herein that aprataxin localizes to mitochondria in human cells and we identify an N-terminal amino acid sequence that targets certain isoforms of the protein to this intracellular compartment. We also show that transcripts encoding this unique N-terminal stretch are expressed in the human brain, with highest production in the cerebellum. Depletion of aprataxin in human SH-SY5Y neuroblastoma cells and primary skeletal muscle myoblasts results in mitochondrial dysfunction, which is revealed by reduced citrate synthase activity and mtDNA copy number. Moreover, mtDNA, not nuclear DNA, was found to have higher levels of background DNA damage on aprataxin knockdown, suggesting a direct role for the enzyme in mtDNA processing.
U2 - 10.1073/pnas.1100084108
DO - 10.1073/pnas.1100084108
M3 - Journal article
C2 - 21502511
VL - 108
SP - 7437
EP - 7442
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 18
ER -
ID: 33492640