title: Inhibitor of growth 1 (ING1) acts at early steps of multiple DNA repair pathways.
abstract: ING proteins are tumor suppressors involved in the regulation of gene transcription, cell cycle arrest, apoptosis, and senescence. Here, we show that ING1b expression is upregulated by several DNA-damaging agents, in a p53-independent manner. ING1b stimulates DNA repair of a variety of DNA lesions requiring activation of multiple DNA repair pathways. Moreover, Ing1(-/-) cells showed impaired genomic DNA repair after H2O2 and neocarzinostatin treatment and this defect was reverted by overexpression of ING1b. Two tumor-derived ING1 mutants failed to promote DNA repair highlighting the physiological importance of the integrity of the PHD domain for ING1b DNA repair activity and suggesting a role in the prevention of tumor progression. Ing(-/-) cells showed higher basal levels of γ-H2AX and, upon DNA damage, γ-H2AX increase was greater and with faster kinetics compared to wild-type cells. Chromatin relaxation by Trichostatin A led to an exacerbated damage signal in both types of cells, but this effect was dependent on Ing1 status, and more pronounced in wild-type cells. Our results suggest that ING1 acts at early stages of the DNA damage response activating a variety of repair mechanisms and that this function of ING1 is targeted in tumors.
authors: Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Consejo Nacional de Investigaciones Científicas y Técnicas, Universidad de Buenos Aires, Buenos Aires, Argentina.
authors: Julieta M
authors: JM
authors: Ceruti
authors: María F
authors: MF
authors: Ogara
authors: Camino
authors: C
authors: Menéndez
authors: Ignacio
authors: I
authors: Palmero
authors: Eduardo T
authors: ET
authors: Cánepa
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D000071877:Checkpoint Kinase 1; D004249:DNA Damage; D004260:DNA Repair; D015870:Gene Expression; D015894:Genome, Human; D042822:Genomic Instability; D006657:Histones / Q000378:metabolism; D006801:Humans; D000076023:Inhibitor of Growth Protein 1; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology*; D051379:Mice; D020125:Mutation, Missense; D009687:Nuclear Proteins / Q000502:physiology*; D020033:Protein Isoforms / Q000502:physiology; D011494:Protein Kinases / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000502:physiology*; D015854:Up-Regulation
chemical_list: D006657:Histones; C501503:ING1 protein, human; D000076023:Inhibitor of Growth Protein 1; D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; D020033:Protein Isoforms; D025521:Tumor Suppressor Proteins; C475961:gamma-H2AX protein, mouse; D011494:Protein Kinases; D000071877:Checkpoint Kinase 1