Chk2 Regulates Irradiation-induced, P53-mediated Apoptosis in Drosophila

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2002 Aug 13

PMID 12172011

Citations 42

Authors

Malte Peters

Carmela DeLuca

Atsushi Hirao

Vuk Stambolic

Julia Potter

Lily Zhou

Jennifer Liepa

Bryan Snow

Sudha Arya

Jorge Wong

Denis Bouchard

Richard Binari

Armen S Manoukian

Tak W Mak

Affiliations

Soon will be listed here.

Abstract

The tumor suppressor function of p53 has been attributed to its ability to regulate apoptosis and the cell cycle. In mammals, DNA damage, aberrant growth signals, chemotherapeutic agents, and UV irradiation activate p53, a process that is regulated by several posttranslational modifications. In Drosophila melanogaster, however, the regulation modes of p53 are still unknown. Overexpression of D. melanogaster p53 (Dmp53) in the eye induced apoptosis, resulting in a small eye phenotype. This phenotype was markedly enhanced by coexpression with D. melanogaster Chk2 (DmChk2) and was almost fully rescued by coexpression with a dominant-negative (DN), kinase-dead form of DmChk2. DN DmChk2 also inhibited Dmp53-mediated apoptosis in response to DNA damage, whereas overexpression of Grapes (Grp), the Drosophila Chk1-homolog, and its DN mutant had no effect on Dmp53-induced phenotypes. DmChk2 also activated the Dmp53 transactivation activity in cultured cells. Mutagenesis of Dmp53 amino terminal Ser residues revealed that Ser-4 is critical for its responsiveness toward DmChk2. DmChk2 activates the apoptotic activity of Dmp53 and Ser-4 is required for this effect. Contrary to results in mammals, Grapes, the Drosophila Chk1-homolog, is not involved in regulating Dmp53. Chk2 may be the ancestral regulator of p53 function.

Citing Articles

Nuclear reassembly defects after mitosis trigger apoptotic and p53-dependent safeguard mechanisms in Drosophila.

Li J, Jordana L, Mehsen H, Wang X, Archambault V PLoS Biol. 2024; 22(8):e3002780.

PMID: 39186808 PMC: 11379398. DOI: 10.1371/journal.pbio.3002780.

Regulation and coordination of the different DNA damage responses in .

Baonza A, Tur-Gracia S, Perez-Aguilera M, Estella C Front Cell Dev Biol. 2022; 10:993257.

PMID: 36147740 PMC: 9486394. DOI: 10.3389/fcell.2022.993257.

Distinct p53 isoforms code for opposing transcriptional outcomes.

Wylie A, Jones A, Das S, Lu W, Abrams J Dev Cell. 2022; 57(15):1833-1846.e6.

PMID: 35820415 PMC: 9378576. DOI: 10.1016/j.devcel.2022.06.015.

Enhanced germline stem cell longevity in Drosophila diapause.

Easwaran S, Van Ligten M, Kui M, Montell D Nat Commun. 2022; 13(1):711.

PMID: 35132083 PMC: 8821637. DOI: 10.1038/s41467-022-28347-z.

Coordination between cell proliferation and apoptosis after DNA damage in Drosophila.

Ruiz-Losada M, Gonzalez R, Peropadre A, Gil-Galvez A, Tena J, Baonza A Cell Death Differ. 2021; 29(4):832-845.

PMID: 34824391 PMC: 8989919. DOI: 10.1038/s41418-021-00898-6.

References

Lakin N, Jackson S . Regulation of p53 in response to DNA damage. Oncogene. 2000; 18(53):7644-55. DOI: 10.1038/sj.onc.1203015. View

Russell P . Checkpoints on the road to mitosis. Trends Biochem Sci. 1998; 23(10):399-402. DOI: 10.1016/s0968-0004(98)01291-2. View

Matsuoka S, Huang M, Elledge S . Linkage of ATM to cell cycle regulation by the Chk2 protein kinase. Science. 1998; 282(5395):1893-7. DOI: 10.1126/science.282.5395.1893. View

Blasina A, de Weyer I, Laus M, Luyten W, Parker A, McGowan C . A human homologue of the checkpoint kinase Cds1 directly inhibits Cdc25 phosphatase. Curr Biol. 1999; 9(1):1-10. DOI: 10.1016/s0960-9822(99)80041-4. View

Rhind N, Russell P . Mitotic DNA damage and replication checkpoints in yeast. Curr Opin Cell Biol. 1999; 10(6):749-58. PMC: 2864141. DOI: 10.1016/s0955-0674(98)80118-x. View

Brodsky M, Nordstrom W, Tsang G, Kwan E, Rubin G, Abrams J . Drosophila p53 binds a damage response element at the reaper locus. Cell. 2000; 101(1):103-13. DOI: 10.1016/S0092-8674(00)80627-3. View

Jin S, Martinek S, Joo W, Wortman J, Mirkovic N, Sali A . Identification and characterization of a p53 homologue in Drosophila melanogaster. Proc Natl Acad Sci U S A. 2000; 97(13):7301-6. PMC: 16540. DOI: 10.1073/pnas.97.13.7301. View

Rhind N, Russell P . Chk1 and Cds1: linchpins of the DNA damage and replication checkpoint pathways. J Cell Sci. 2000; 113 ( Pt 22):3889-96. PMC: 2863124. DOI: 10.1242/jcs.113.22.3889. View

Walworth N . Cell-cycle checkpoint kinases: checking in on the cell cycle. Curr Opin Cell Biol. 2000; 12(6):697-704. DOI: 10.1016/s0955-0674(00)00154-x. View

10.

Higashitani A, Aoki H, Mori A, Sasagawa Y, Takanami T, Takahashi H . Caenorhabditis elegans Chk2-like gene is essential for meiosis but dispensable for DNA repair. FEBS Lett. 2000; 485(1):35-9. DOI: 10.1016/s0014-5793(00)02178-5. View

11.

Zhou B, Elledge S . The DNA damage response: putting checkpoints in perspective. Nature. 2000; 408(6811):433-9. DOI: 10.1038/35044005. View

12.

Vousden K . p53: death star. Cell. 2000; 103(5):691-4. DOI: 10.1016/s0092-8674(00)00171-9. View

13.

MacQueen A, Villeneuve A . Nuclear reorganization and homologous chromosome pairing during meiotic prophase require C. elegans chk-2. Genes Dev. 2001; 15(13):1674-87. PMC: 312723. DOI: 10.1101/gad.902601. View

14.

Xu J, Xin S, Du W . Drosophila Chk2 is required for DNA damage-mediated cell cycle arrest and apoptosis. FEBS Lett. 2001; 508(3):394-8. DOI: 10.1016/s0014-5793(01)03103-9. View

15.

Kohler G, Milstein C . Continuous cultures of fused cells secreting antibody of predefined specificity. Nature. 1975; 256(5517):495-7. DOI: 10.1038/256495a0. View

16.

Brand A, Perrimon N . Targeted gene expression as a means of altering cell fates and generating dominant phenotypes. Development. 1993; 118(2):401-15. DOI: 10.1242/dev.118.2.401. View

17.

Cho Y, Gorina S, Jeffrey P, Pavletich N . Crystal structure of a p53 tumor suppressor-DNA complex: understanding tumorigenic mutations. Science. 1994; 265(5170):346-55. DOI: 10.1126/science.8023157. View

18.

Hari K, Santerre A, Sekelsky J, McKim K, Boyd J, Hawley R . The mei-41 gene of D. melanogaster is a structural and functional homolog of the human ataxia telangiectasia gene. Cell. 1995; 82(5):815-21. DOI: 10.1016/0092-8674(95)90478-6. View

19.

Shieh S, Ahn J, Tamai K, Taya Y, Prives C . The human homologs of checkpoint kinases Chk1 and Cds1 (Chk2) phosphorylate p53 at multiple DNA damage-inducible sites. Genes Dev. 2000; 14(3):289-300. PMC: 316358. View

20.

Hirao A, Kong Y, Matsuoka S, Wakeham A, Ruland J, Yoshida H . DNA damage-induced activation of p53 by the checkpoint kinase Chk2. Science. 2000; 287(5459):1824-7. DOI: 10.1126/science.287.5459.1824. View