Induction of ASAP (MAP9) contributes to p53 stabilization in response to DNA damage.
p53 is a key tumor suppressor that controls DNA damage response and genomic integrity. In response to genotoxic stress, p53 is stabilized and activated, resulting in controlled activation of genes involved in cell cycle arrest, DNA repair and/or apoptosis. ASAP is a centrosome- and spindle-associated protein, the deregulation of which induces severe mitotic defects. We show here that following double-strand break DNA formation, ASAP directly interacts with and stabilizes p53 by enhancing its p300-mediated acetylation and blocking its MDM2-mediated ubiquitination and degradation, leading to an increase of p53 transcriptional activity. Upon DNA damage, ASAP is transiently accumulated before being degraded upon persistent damage. This work links the p53 response with the cytoskeleton and confirms that the DNA-damaging signaling pathway is coordinated by centrosomal proteins. We reveal the existence of a new pathway through which ASAP signals the DNA damage response by regulating the p300-MDM2-p53 loop. These results point out ASAP as a possible target for the design of drugs to sensitize radio-resistant tumors.
Groupe Microtubules et Cycle Cellulaire, Institut de Génétique Humaine, CNRS UPR 1142, Montpellier, France.
Jihane
J
Basbous
Dora
D
Knani
Nathalie
N
Bonneaud
Dominique
D
Giorgi
Jean-Marc
JM
Brondello
Sylvie
S
Rouquier
D000107:Acetylation; D059447:Cell Cycle Checkpoints; D045744:Cell Line, Tumor; D004249:DNA Damage; D050881:E1A-Associated p300 Protein / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D008869:Microtubule-Associated Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination
C505827:MAP9 protein, human; D008869:Microtubule-Associated Proteins; D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53; D050881:E1A-Associated p300 Protein; C494360:EP300 protein, human; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2