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Nucleic Acids Res. 2009 Jun;37(10):3452-63. doi: 10.1093/nar/gkp194. Epub 2009 Apr 1.

Involvement of Exo1b in DNA damage-induced apoptosis.

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1
Signal Transduction Laboratory, Queensland Institute of Medical Research, Brisbane, Queensland 4006, Australia.

Abstract

Apoptosis is essential for the maintenance of inherited genomic integrity. During DNA damage-induced apoptosis, mechanisms of cell survival, such as DNA repair are inactivated to allow cell death to proceed. Here, we describe a role for the mammalian DNA repair enzyme Exonuclease 1 (Exo1) in DNA damage-induced apoptosis. Depletion of Exo1 in human fibroblasts, or mouse embryonic fibroblasts led to a delay in DNA damage-induced apoptosis. Furthermore, we show that Exo1 acts upstream of caspase-3, DNA fragmentation and cytochrome c release. In addition, induction of apoptosis with DNA-damaging agents led to cleavage of both isoforms of Exo1. The cleavage of Exo1 was mapped to Asp514, and shown to be mediated by caspase-3. Expression of a caspase-3 cleavage site mutant form of Exo1, Asp514Ala, prevented formation of the previously observed fragment without any affect on the onset of apoptosis. We conclude that Exo1 has a role in the timely induction of apoptosis and that it is subsequently cleaved and degraded during apoptosis, potentially inhibiting DNA damage repair.

PMID:
19339515
PMCID:
PMC2691832
DOI:
10.1093/nar/gkp194
[Indexed for MEDLINE]
Free PMC Article
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