Format

Send to

Choose Destination
See comment in PubMed Commons below
Cell Cycle. 2011 Jul 1;10(13):2218-32. Epub 2011 Jul 1.

MRE11 promotes AKT phosphorylation in direct response to DNA double-strand breaks.

Author information

1
Campbell Family Cancer Research Institute/Ontario Cancer Institute, Toronto, Ontario, Canada.

Abstract

AKT is hyper-activated in many human cancers and promotes proliferation and cancer cell survival in response to DNA damaging agents. Ionizing radiation (IR) produces DNA double strand breaks (DSB) and activates AKT, however a direct mechanism linking intra-nuclear DSB and AKT signaling is lacking. Here we demonstrate that AKT is phosphorylated following IR in benign and malignant cells and, using colony-forming assays and in vitro rejoining assays, show that AKT promotes non-homologous end joining-mediated DSB repair and cell survival following IR. Further studies revealed that pAKT-S473, but not pAKT-T308 or total AKT, accumulates in the vicinity of IR-induced DSB and co-localizes with γH2AX and ATM-pSer1981. Based on whole-cell IR, nuclear UV microbeam, and endonuclease-induced DSB studies, we observed that pAKT-S473 is up-regulated by a DSB-induced signaling cascade, and this is dependent on the DSB sensor protein, MRE11. MRE11-dependent pAKT-S473 did not require the MRE11 endonuclease domain. The histone ubiquitin ligase RNF168 is also required for DSB-induced pAKT-S473, and DSB-induced pAKT-S473 is independent of DNA-PKcs, PI3K, and ATR. These data demonstrate that DSB activate a signaling cascade that directly promotes a PI3K-independent pathway of AKT phosphorylation that is dependent on MRE11-ATM-RNF168 signaling. Thus, these data directly link the presence of DNA breaks to AKT-mediated cell survival and support AKT as a target for cancer therapy.

PMID:
21623170
DOI:
10.4161/cc.10.13.16305
[Indexed for MEDLINE]
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for Taylor & Francis
    Loading ...
    Support Center