1. ¹Department of Biochemistry & Molecular Biology, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd. – Unit 1000, Houston, TX, USA
2. ²The Genes & Development Graduate Program (http://www.mdanderson.org/genedev)

Correspondence: A Bergmann, Department of Biochemistry & Molecular Biology, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd. – Unit 1000, Houston, TX 77030, USA. Tel: +(1) 713 834 6294; Fax: +(1) 713 834 6291; E-mail: abergman@mdanderson.org

Received 3 February 2006; Revised 14 February 2006; Accepted 14 February 2006; Published online 28 April 2006.

Abstract

In mammals and Drosophila, apoptotic caspases are under positive control of the CED-4-like proteins Apaf-1 and ARK, respectively. In an EMS-mutagenesis screen, we isolated 33 ark mutants as recessive suppressors of hid-induced apoptosis. The ark mutants are loss-of-function alleles characterized by reduced developmental apoptosis. Using the phenotypic series of these alleles, we identified helical domain I in the nucleotide oligomerization domain as critical for ARK's apoptotic activity. Interestingly, the WD40 region may also have an unanticipated positive requirement for the apoptotic activity of ARK. Considering structural information, we discuss the roles of these domains for assembly and activity of the ARK apoptosome, and propose that the WD40 region is anti-apoptotic in the absence of apoptotic signals, and pro-apoptotic in the presence of such signals. Furthermore, a defined null allele reveals that ark is required for most, but not all apoptosis suggesting the existence of an ARK-independent apoptotic pathway.