TIP49b, a regulator of activating transcription factor 2 response to stress and DNA damage

Activating transcription factor 2 (ATF2/CRE-BP1) is implicated in transcrip tional control of stress-responsive genes. A yeast two-hybrid screen identi fied TBP-interacting protein 49b (TIP49b), a component of the INO80 chromat in-remodeling complex, as a novel ATF2-interacting protein. TIP49b's associ ation with ATF2 is phosphorylation dependent and requires amino acids 150 t o 248 of ATF2 (ATF2(150-248)), which are implicated in intramolecular inhib ition of ATF2 transcriptional activities. Forced expression of TIP49b effic iently attenuated ATF2 transcriptional activities under normal growth condi tions as well as after UV treatment, ionizing irradiation, or activation of p38 kinase, all of which induced ATF2 phosphorylation and increased TIP49b -ATF2 association. Constitutive expression of ATF2(150-248) peptide outcomp eted TIP49b interaction with ATF2 and alleviated the suppression of ATF2 tr anscriptional activities. Expression of ATF2(150-248) in fibroblasts or mel anoma but not in ATF2-null cells caused a profound G(2)M arrest and increas ed degree of apoptosis following irradiation. The interaction between ATF2 and TIP49b constitutes a novel mechanism that serves to limit ATF2 transcri ptional activities and highlights the central role of ATF2 in the control o f the cell cycle and apoptosis in response to stress and DNA damage.