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 Posted: Tue Jul 29, 2008 9:40 pm Post subject: WRN Exonuclease activity is blocked by specific oxidatively |
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Nucleic Acids Res. 2008 Jul 25. [Epub ahead of print]
WRN Exonuclease activity is blocked by specific oxidatively induced
base lesions positioned in either DNA strand.Bukowy Z, Harrigan JA,
Ramsden DA, Tudek B, Bohr VA, Stevnsner T.
Danish Centre for Molecular Gerontology, Department of Molecular
Biology, University of Aarhus, Denmark, Laboratory of Molecular
Gerontology, National Institute on Aging, National Institutes of
Health, Baltimore, MD 21224, USA, Department of Biochemistry and
Biophysics, University of North Carolina at Chapel Hill, Chapel Hill,
NC 27599, USA, Institute of Biochemistry and Biophysics, Polish
Academy of Sciences, Warsaw and Institute of Genetics and
Biotechnology, Warsaw University, Warsaw, Poland.
Werner syndrome (WS) is a premature aging disorder caused by mutations
in the WS gene (WRN). Although WRN has been suggested to play an
important role in DNA metabolic pathways, such as recombination,
replication and repair, its precise role still remains to be
determined. WRN possesses ATPase, helicase and exonuclease activities.
Previous studies have shown that the WRN exonuclease is inhibited in
vitro by certain lesions induced by oxidative stress and positioned in
the digested strand of the substrate. The presence of the 70/86 Ku
heterodimer (Ku), participating in the repair of double-strand breaks
(DSBs), alleviates WRN exonuclease blockage imposed by the oxidatively
induced DNA lesions. The current study demonstrates that WRN
exonuclease is inhibited by several additional oxidized bases, and
that Ku stimulates the WRN exonuclease to bypass these lesions.
Specific lesions present in the non-digested strand were shown also to
inhibit the progression of the WRN exonuclease; however, Ku was not
able to stimulate WRN exonuclease to bypass these lesions. Thus, this
study considerably broadens the spectrum of lesions which block WRN
exonuclease progression, shows a blocking effect of lesions in the non-
digested strand, and supports a function for WRN and Ku in a DNA
damage processing pathway.
PMID: 18658245 [PubMed - as supplied by publisher] |
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