The E1A-associated p400 protein modulates cell fate decisions by the regulation of ROS homeostasis.
The p400 E1A-associated protein, which mediates H2A.Z incorporation at specific promoters, plays a major role in cell fate decisions: it promotes cell cycle progression and inhibits induction of apoptosis or senescence. Here, we show that p400 expression is required for the correct control of ROS metabolism. Depletion of p400 indeed increases intracellular ROS levels and causes the appearance of DNA damage, indicating that p400 maintains oxidative stress below a threshold at which DNA damages occur. Suppression of the DNA damage response using a siRNA against ATM inhibits the effects of p400 on cell cycle progression, apoptosis, or senescence, demonstrating the importance of ATM-dependent DDR pathways in cell fates control by p400. Finally, we show that these effects of p400 are dependent on direct transcriptional regulation of specific promoters and may also involve a positive feedback loop between oxidative stress and DNA breaks since we found that persistent DNA breaks are sufficient to increase ROS levels. Altogether, our results uncover an unexpected link between p400 and ROS metabolism and allow deciphering the molecular mechanisms largely responsible for cell proliferation control by p400.
Mattera
Lise
L
Laboratoire de Biologie Cellulaire et Moléculaire du Contrôle de la Prolifération, CNRS and Université de Toulouse, Toulouse, France.
Courilleau
Céline
C
Legube
Gaëlle
G
Ueda
Takeshi
T
Fukunaga
Rikiro
R
Chevillard-Briet
Martine
M
Canitrot
Yvan
Y
Escaffit
Fabrice
F
Trouche
Didier
D
D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004249:DNA Damage; D004265:DNA Helicases / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D006706:Homeostasis; D006801:Humans; D020411:Oligonucleotide Array Sequence Analysis; D018384:Oxidative Stress; D034741:RNA, Small Interfering / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction; D014158:Transcription, Genetic
D004268:DNA-Binding Proteins; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D004265:DNA Helicases; C498558:EP400 protein, human