title: Involvement of Exo1b in DNA damage-induced apoptosis.
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.
authors.affiliation: Signal Transduction Laboratory, Queensland Institute of Medical Research, Brisbane, Queensland 4006, Australia.
authors.forename: Emma
authors.initials: E
authors.lastname: Bolderson
authors.forename: Derek J
authors.initials: DJ
authors.lastname: Richard
authors.forename: Winfried
authors.initials: W
authors.lastname: Edelmann
authors.forename: Kum Kum
authors.initials: KK
authors.lastname: Khanna