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Science Forum Index » Life Extension Forum » Removal of Oxidative DNA Damage via FEN1-Dependent...
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 Posted: Wed Jun 11, 2008 10:14 am |
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Mol Cell Biol. 2008 Jun 9. [Epub ahead of print]
Removal of Oxidative DNA Damage via FEN1-Dependent Long-Patch Base
Excision Repair in Human Cell Mitochondria.Liu P, Qian L, Sung JS, de
Souza-Pinto NC, Zheng L, Bogenhagen DF, Bohr VA, Wilson DM 3rd, Shen
B, Demple B.
Department of Genetics and Complex Diseases, Harvard School of Public
Health, Boston, Massachusetts 02115, USA; Department of Radiation
Biology, City of Hope National Medical Center and Beckman Research
Institute, Duarte, California 91010, USA; Department of Biology,
Dongguk University, Seoul 100-715, South Korea; Laboratory of
Molecular Gerontology, National Institute on Aging, National
Institutes of Health, Baltimore, Maryland 21224, USA; Department of
Pharmacological Sciences, State University of New York at Stony Brook,
Stony Brook, New York 11794-8651, USA.
Repair of oxidative DNA damage in mitochondria was thought limited to
short-patch base excision repair (SP-BER) replacing a single
nucleotide. However, certain oxidative lesions cannot be processed by
SP-BER. Here we report that 2-deoxyribonolactone (dL), a major type of
oxidized abasic site, inhibits replication by mitochondrial DNA
polymerase gamma and interferes with SP-BER by covalently trapping
polymerase gamma during attempted dL excision. However, repair of dL
was detected in human mitochondrial extracts, which we show is via
long-patch BER (LP-BER) dependent on flap endonuclease 1 (FEN1), not
previously known to be present in mitochondria. FEN1 was retained in
protease-treated mitochondria and detected in mitochondrial nucleoids
that contain known mitochondrial replication and transcription
proteins. Immunofluoresence and subcellular fractionation studies were
also consistent with FEN1 in the mitochondria of intact cells.
Immunodepletion experiments showed that the LP-BER activity of
mitochondrial extracts was strongly diminished in parallel with the
removal of FEN1, although some activity remained, suggesting the
presence of an additional flap-removing enzyme. Biological evidence
for a FEN1 role in repairing mitochondrial oxidative DNA damage was
provided by RNA-interference experiments, with the extent of damage
greater and the recovery slower in FEN1-depleted than in control
cells. The mitochondrial LP-BER pathway likely plays important roles
in repairing dL and other oxidative lesions, and perhaps in normal
mtDNA replication.
PMID: 18541666 [PubMed - as supplied by publisher] |
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