The anti-apoptotic factor Che-1/AATF links transcriptional regulation, cell cycle control, and DNA damage response

Claudio Passananti,Maurizio Fanciulli

doi:10.1186/1747-1028-2-21

Abstract

Che-1 is a RNA polymerase II binding protein involved in the transcriptional regulation of E2F target genes and in cell proliferation. Recently, it has been shown that Che-1 accumulates in cells responding to genotoxic agents such as Doxorubicin and ionizing radiation. The DNA damage-activated checkpoint kinases ATM and Chk2 interact with and phosphorylate Che-1, enhancing its accumulation and stability, and promoting Che-1-mediated transcription of p53-responsive genes and of p53 itself, as evidenced by microarray analysis. This transcriptional response is suppressed by expression of a Che-1 mutant lacking ATM and Chk2 phosphorylation amino acid residues, or by depletion of Che-1 by RNA silencing. In addition, chromatin immunoprecipitation analysis has shown that Che-1 is released from E2F target genes and recruited to the p21 and p53 promoters after DNA damage. Che-1 contributes to the maintenance of the G2/M checkpoint in response to genotoxic stress. These findings identify a new mechanism by which the checkpoint kinases regulate, via the novel effector Che-1, the p53 pathway. Lastly, increasing evidence suggests that Che-1 may be involved in apoptotic signaling in neural tissues. In cortical neurons, Che-1 exhibits anti-apoptotic activity, protecting cells from neuronal damage induced by amyloid β-peptide. In cerebellar granule neurons, Che-1 interacts with Tau in the cytoplasmic compartment and this interaction is modulated during neuronal apoptosis. Finally, Che-1 directly interacts with the neuronal cell-death inducer "NRAGE" which downregulates endogenous Che-1 by targeting it for proteasome-dependent degradation. These findings identify Che-1 as a novel cytoprotective factor against apoptotic insults and suggest that Che-1 may represent a potential target for therapeutic application.

Highlights

Che-1, called AATF or Ded, is a phosphoprotein containing 558 amino acids and has been identified as a RNA polymerase II binding protein in a two-hybrid screen [1]
Che-1 is a RNA polymerase II binding protein involved in the transcriptional regulation of E2F target genes and in cell proliferation
Che-1 interacts with Tau in the cytoplasmic compartment and this interaction is modulated during neuronal apoptosis

Summary

Background

Che-1, called AATF or Ded, is a phosphoprotein containing 558 amino acids and has been identified as a RNA polymerase II binding protein in a two-hybrid screen [1]. Chromatin immunoprecipitation experiments revealed that in response to DNA damage, Che-1 phosphorylation displaces it from E2F target genes and increases its occupancy at the p21 and TP53 promoters From these findings it is possible to propose a model in which, in response to genotoxic stress, a molecular switch moves Che-1 from a cell cycle progression pathway to growth arrest of the cell. It is reasonable to speculate that Che-1 may be a component of the anticancer barrier that protects cells from DNA damage or oncogenic stress [14,15] by inducing cellular senescence [16,17] Consistent with this hypothesis, Che-1 contains a conserved motif (EExxxDDL) required by several important proteins involved in the DNA damage response, such as NSB1, Ku80 and ATRIP, for their interaction with ATM, DNAPKcs, and ATR, respectively [18].

Concluding remarks

10. Shiloh Y