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Molecular and Cellular Biology, February 2004, p. 1219-1231, Vol. 24, No. 3
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.3.1219-1231.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Drosophila melanogaster MNK/Chk2 and p53 Regulate Multiple DNA Repair and Apoptotic Pathways following DNA Damage

Michael H. Brodsky,1,2* Brian T. Weinert,2 Garson Tsang,2,3 Yikang S. Rong,4 Nadine M. McGinnis,1 Kent G. Golic,5 Donald C. Rio,2 and Gerald M. Rubin2,3

Program in Gene Function and Expression and Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605,1 Department of Molecular and Cell Biology, University of California, Berkeley, California 94720-3200,2 Howard Hughes Medical Institute,3 Department of Biology, University of Utah, Salt Lake City, Utah 84112,5 Laboratory of Molecular Cell Biology, National Cancer Institute, Bethesda, Maryland 208924

Received 20 June 2003/ Returned for modification 6 August 2003/ Accepted 3 October 2003

We have used genetic and microarray analysis to determine how ionizing radiation (IR) induces p53-dependent transcription and apoptosis in Drosophila melanogaster. IR induces MNK/Chk2-dependent phosphorylation of p53 without changing p53 protein levels, indicating that p53 activity can be regulated without an Mdm2-like activity. In a genome-wide analysis of IR-induced transcription in wild-type and mutant embryos, all IR-induced increases in transcript levels required both p53 and the Drosophila Chk2 homolog MNK. Proapoptotic targets of p53 include hid, reaper, sickle, and the tumor necrosis factor family member Eiger. Overexpression of Eiger is sufficient to induce apoptosis, but mutations in Eiger do not block IR-induced apoptosis. Animals heterozygous for deletions that span the reaper, sickle, and hid genes exhibited reduced IR-dependent apoptosis, indicating that this gene complex is haploinsufficient for induction of apoptosis. Among the genes in this region, hid plays a central, dosage-sensitive role in IR-induced apoptosis. p53 and MNK/Chk2 also regulate DNA repair genes, including two components of the nonhomologous end-joining repair pathway, Ku70 and Ku80. Our results indicate that MNK/Chk2-dependent modification of Drosophila p53 activates a global transcriptional response to DNA damage that induces error-prone DNA repair as well as intrinsic and extrinsic apoptosis pathways.

* Corresponding author. Mailing address: Program in Gene Function and Expression and Program in Molecular Medicine, 623, LRB, University of Massachusetts Medical School, Worcester, MA 01605. Phone: (508) 856-1640. Fax: (508) 856-5460. E-mail: michael.brodsky{at}umassmed.edu.

Molecular and Cellular Biology, February 2004, p. 1219-1231, Vol. 24, No. 3
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.3.1219-1231.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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