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Nucleic Acids Research Advance Access published online on April 1, 2009
Nucleic Acids Research, doi:10.1093/nar/gkp194
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© 2009 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Genome Integrity, Repair, and Replication

Involvement of Exo1b in DNA damage-induced apoptosis

Emma Bolderson1, Derek J. Richard1, Winfried Edelmann2 and Kum Kum Khanna1,*

1Signal Transduction Laboratory, Queensland Institute of Medical Research, Brisbane, Queensland 4006, Australia and 2Department of Cell Biology, Albert Einstein College of Medicine, Bronx, New York 10461, USA

*To whom correspondence should be addressed. Tel: +61 7 3362 0338; Fax: +61 7 3362 0105; Email: Kumkumk{at}qimr.edu.au

Received December 8, 2008. Revised February 18, 2009. Accepted March 10, 2009.

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.


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