Regulation of TIP60 by ATF2 Modulates ATM Activation^*

^‡Signal Transduction Program, Burnham Institute for Medical Research, La Jolla, California 92037 and the ^§Department of Oncological Sciences, Mount Sinai School of Medicine, New York, New York 10029

↵1 To whom correspondence should be addressed. Tel.: 858-646-3185; E-mail: ronai{at}burnham.org.

Abstract

TIP60 (HTATIP) is a histone acetyltransferase (HAT) whose function is critical in regulating ataxia-telangiectasia mutated (ATM) activation, gene expression, and chromatin acetylation in DNA repair. Here we show that under non-stressed conditions, activating transcription factor-2 (ATF2) in cooperation with Cul3 ubiquitin ligase promotes degradation of TIP60, thereby attenuating its HAT activity. Inhibiting either ATF2 or Cul3 expression by small interfering RNA stabilizes the TIP60 protein. ATF2 association with TIP60 on chromatin is decreased following exposure to ionizing radiation (IR), resulting in enhanced TIP60 stability and activity. We also identified a panel of melanoma and prostate cancer cell lines whose ATF2 expression is inversely correlated with TIP60 levels and ATM activation after IR. Inhibition of ATF2 expression in these lines restored TIP60 protein levels and both basal and IR-induced levels of ATM activity. Our study provides novel insight into regulation of ATM activation by ATF2-dependent control of TIP60 stability and activity.

Footnotes

↵^* This work was supported, in whole or in part, by National Institutes of Health Grants CA 099961 (to Z. R.) and CA100076 (to M. O. C.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
↵ The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1-S4.