Genetic Link between Heme Oxygenase and the Signaling Pathway of DNA Damage in Drosophila Melanogaster

Genetic Link between Heme Oxygenase and the Signaling Pathway of DNA Damage in Drosophila Melanogaster

HIROYUKI IDA,¹ OSAMU SUYARI,^2,3 MAI SHIMAMURA,¹ TRAN TIEN TAI,² MASAMITSU YAMAGUCHI^1,3 and SHIGERU TAKETANI^2,3

¹Department of Applied Biology, Kyoto Institute of Technology, Kyoto, Kyoto, Japan
²Department of Biotechnology, Kyoto Institute of Technology, Kyoto, Kyoto, Japan
³Insect Biomedical Research Center, Kyoto Institute of Technology, Kyoto, Kyoto, Japan

Heme oxygenase (HO) is a rate-limiting step of heme degradation, which catalyzes the conversion of heme into biliverdin, iron, and CO. HO has been characterized in microorganisms, insects, plants, and mammals. The mammalian enzyme participates in adaptive and protective responses to oxidative stress and various inflammatory stimuli. The present study reports that eye imaginal disc-specific knockdown of the Drosophila HO homologue (dHO) conferred serious abnormal eye morphology in adults, resulting in the generation of reactive oxygen species and apoptosis in third-instar larvae. Oxidative stress frequently induces DNA lesions that are recognized by damage sensors, including ataxia-telangiectasia mutated (ATM) and ataxia-telangiectasia and rad3-related (ATR) proteins. The knockdown of dHO took place in G0/G1-arrested cells posterior to the morphogenetic furrow and thus prevented these cells from entering S-phase, with an increase in the level of histone H2A.V, a DNA damage marker. Moreover, the knockdown of dHO resulted in the enhancement of the rough eye phenotype in ATM-deficient flies or was lethal in ATR-deficient flies. These results indicate that dHO functions in control of the signal pathway of DNA damage. On the other hand, genetic crosses with a collection of Drosophila deficiency stocks allowed us to identify eight genomic regions, each deletion of which caused suppression of the rough eye phenotype induced by dHO knockdown. This information should facilitate the identification of HO regulators in Drosophila and clarification of the roles of HO in eye development.

keywords —— ataxia-telangiectasia mutated; DNA damage; Drosophila melanogaster; genetic interaction; heme oxygenase

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Tohoku J. Exp. Med., 2013, 231, 117-125

Correspondence: Shigeru Taketani, Department of Biotechnology, Kyoto Institute of Technology, Matsugasaki, Sakyo-ku, Kyoto, Kyoto 606-8585, Japan.

e-mail: taketani@kit.ac.jp