title: Heme oxygenase-1 and carbon monoxide modulate DNA repair through ataxia-telangiectasia mutated (ATM) protein.
abstract: Stability and repair of DNA is of principal importance in cell survival. Heme oxygenase-1 (HO-1; Hmox1) is critical in maintaining cellular homeostasis, in large part through its ability to generate CO, but neither molecule has been studied in the setting of DNA damage. Naïve Hmox1(-/-) mice exhibit excessive tissue levels of γ-histone H2A, whereas administration of genotoxic stressors or irradiation in HO-1-deficient cells resulted in loss of ataxia-telangiectasia mutated/ataxia telangiectasia and Rad3-related protein and breast cancer 1, early onset induction with dysfunctional γ-H2AX foci and marked elevations in DNA damage. HO-1 induction or exposure to CO induced homologous recombination-mediated DNA repair through ataxia-telangiectasia mutated/ataxia telangiectasia and Rad3-related protein. In vivo, exposure of mice to CO followed by genotoxin (Adriamycin) or radiation-induced injury led to diminished tissue DNA damage and improved survival. We characterize a joint role for HO-1 and the gasotransmitter CO for appropriate DNA repair and provide a mechanism for their potent cytoprotective effects in various pathologies.
authors.affiliation: Transplant Institute, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Leo E
authors.initials: LE
authors.lastname: Otterbein
authors.forename: Andreas
authors.initials: A
authors.lastname: Hedblom
authors.forename: Clair
authors.initials: C
authors.lastname: Harris
authors.forename: Eva
authors.initials: E
authors.lastname: Csizmadia
authors.forename: David
authors.initials: D
authors.lastname: Gallo
authors.forename: Barbara
authors.initials: B
authors.lastname: Wegiel
mesh_terms: D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D002248:Carbon Monoxide / Q000494:pharmacology*; D018797:Cell Cycle Proteins / Q000502:physiology*; D004247:DNA / Q000378:metabolism*; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000502:physiology*; D004317:Doxorubicin / Q000494:pharmacology; D051547:Heme Oxygenase-1 / Q000502:physiology*; D006657:Histones / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects; D025521:Tumor Suppressor Proteins / Q000502:physiology*
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D006657:Histones; D008565:Membrane Proteins; D025521:Tumor Suppressor Proteins; C475961:gamma-H2AX protein, mouse; D002248:Carbon Monoxide; D004317:Doxorubicin; D004247:DNA; D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse; C576897:Atr protein, mouse; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases