Regulation of TIP60 by ATF2 modulates ATM activation.
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.
Bhoumik
Anindita
A
Signal Transduction Program, Burnham Institute for Medical Research, La Jolla, California 92037, USA.
Singha
Netai
N
O'Connell
Matthew J
MJ
Ronai
Ze'ev A
ZA
D051698:Activating Transcription Factor 2 / Q000378:metabolism*; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D002843:Chromatin / Q000378:metabolism; D044842:Cullin Proteins / Q000378:metabolism; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005786:Gene Expression Regulation; D015972:Gene Expression Regulation, Neoplastic; D006367:HeLa Cells; D051548:Histone Acetyltransferases / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D000074443:Lysine Acetyltransferase 5; D008954:Models, Biological; D008957:Models, Genetic; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D034622:RNA Interference; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
C497105:ATF2 protein, human; D051698:Activating Transcription Factor 2; C503645:CUL3 protein, human; D018797:Cell Cycle Proteins; D002843:Chromatin; D044842:Cullin Proteins; D004268:DNA-Binding Proteins; D025521:Tumor Suppressor Proteins; D051548:Histone Acetyltransferases; C098489:KAT5 protein, human; D000074443:Lysine Acetyltransferase 5; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases