Inhibitor of growth 1 (ING1) acts at early steps of multiple DNA repair pathways

et al.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.This study was supported by research grants from Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Agencia Nacional de Promoción Científica y Tecnológica (ANPCYT), and Universidad de Buenos Aires to EC and Spanish Ministry of Science and Innovation to IP (SAF2009-09031).Peer reviewe

Inhibitor of growth 1 (ING1) acts at early steps of multiple DNA repair pathways

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.Fil: Ceruti, Julieta María. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica; Argentina; Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Química Biológica; Argentina;Fil: Ogara, Maria Florencia. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Química Biológica; Argentina; Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica; Argentina;Fil: Menéndez, Camino. Instituto de Investigaciones Biomédicas ‘‘Alberto Sols’’; España;Fil: Palmero, Ignacio. Instituto de Investigaciones Biomédicas ‘‘Alberto Sols’’; España;Fil: Canepa, Eduardo Tomas. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Química Biológica; Argentina; Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica; Argentina