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

Claudio Passananti, Maurizio Fanciulli

Research output: Contribution to journalArticle

23 Citations (Scopus)

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.

Original languageEnglish
Article number21
JournalCell Division
Volume2
DOIs
Publication statusPublished - Jul 16 2007

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Cell Cycle Checkpoints
DNA Damage
Genes
Cells
Automatic teller machines
Neurons
DNA
Phosphotransferases
Phosphorylation
Chromatin Immunoprecipitation
Ionizing radiation
p53 Genes
Cell proliferation
Cell death
Proteasome Endopeptidase Complex
Transcription
Microarray Analysis
Microarrays
RNA Interference
Ionizing Radiation

ASJC Scopus subject areas

  • Cell Biology
  • Biochemistry
  • Molecular Biology

Cite this

The anti-apoptotic factor Che-1/AATF links transcriptional regulation, cell cycle control, and DNA damage response. / Passananti, Claudio; Fanciulli, Maurizio.

In: Cell Division, Vol. 2, 21, 16.07.2007.

Research output: Contribution to journalArticle

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