Report

Induction of ASAP (MAP9) contributes to p53 stabilization in response to DNA damage

Volume 11, Issue 12   June 15, 2012
Pages 2380 - 2390
http://dx.doi.org/10.4161/cc.20858
Keywords: DNA damage, Mdm2, microtubule-associated protein ASAP, p300, p53
Authors: Jihane Basbous, Dora Knani, Nathalie Bonneaud, Dominique Giorgi, Jean-Marc Brondello and Sylvie Rouquier

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Abstract:
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.

Received: April 27, 2012; Accepted: May 23, 2012

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