title: KDM5 interacts with Foxo to modulate cellular levels of oxidative stress.
abstract: Increased cellular levels of oxidative stress are implicated in a large number of human diseases. Here we describe the transcription co-factor KDM5 (also known as Lid) as a new critical regulator of cellular redox state. Moreover, this occurs through a novel KDM5 activity whereby it alters the ability of the transcription factor Foxo to bind to DNA. Our microarray analyses of kdm5 mutants revealed a striking enrichment for genes required to regulate cellular levels of oxidative stress. Consistent with this, loss of kdm5 results in increased sensitivity to treatment with oxidizers, elevated levels of oxidized proteins, and increased mutation load. KDM5 activates oxidative stress resistance genes by interacting with Foxo to facilitate its recruitment to KDM5-Foxo co-regulated genes. Significantly, this occurs independently of KDM5's well-characterized demethylase activity. Instead, KDM5 interacts with the lysine deacetylase HDAC4 to promote Foxo deacetylation, which affects Foxo DNA binding.
authors.affiliation: Department of Genetics, Albert Einstein College of Medicine, Bronx, New York, United States of America.
authors.forename: Xingyin
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Genetics, Albert Einstein College of Medicine, Bronx, New York, United States of America.
authors.forename: Christina
authors.initials: C
authors.lastname: Greer
authors.affiliation: Department of Genetics, Albert Einstein College of Medicine, Bronx, New York, United States of America.
authors.forename: Julie
authors.initials: J
authors.lastname: Secombe
mesh_terms: D000107:Acetylation; D000818:Animals; D030801:Animals, Genetically Modified; D001665:Binding Sites; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism; D056466:Histone Demethylases / Q000235:genetics / Q000378:metabolism*; D007814:Larva; D008297:Male; D009154:Mutation; D059645:Mutation Rate; D018384:Oxidative Stress; D011401:Promoter Regions, Genetic
chemical_list: D029721:Drosophila Proteins; C477334:FOXO protein, Drosophila; D051858:Forkhead Transcription Factors; D056466:Histone Demethylases; C518655:Lid protein, Drosophila; C559672:HDAC4 protein, Drosophila; D006655:Histone Deacetylases