Cdx2 homeoprotein inhibits non-homologous end joining in colon cancer but not in leukemia cells.

Abstract

Cdx2, a gene of the paraHox cluster, encodes a homeodomain transcription factor that plays numerous roles in embryonic development and in homeostasis of the adult intestine. Whereas Cdx2 exerts a tumor suppressor function in the gut, its abnormal ectopic expression in acute leukemia is associated to a pro-oncogenic function. To try to understand this duality, we have hypothesized that Cdx2 may interact with different protein partners in the two tissues and set up experiments to identify them by tandem affinity purification. We show here that Cdx2 interacts with the Ku heterodimer specifically in intestinal cells, but not in leukemia cells, via its homeodomain. Ku proteins do not affect Cdx2 transcriptional activity. However, Cdx2 inhibits in vivo and in vitro the DNA repair activity mediated by Ku proteins in intestinal cells. Whereas Cdx2 does not affect the recruitment of Ku proteins and DNA-PKcs into the DNA repair complex, it inhibits DNA-PKcs activity. Thus, we report here a new function of Cdx2, acting as an inhibitor of the DNA repair machinery, that may contribute to its tumor suppressor function specifically in the gut.

• Authors: Benjamin Renouf, Christine Soret, Thoueiba Saandi, François Delalande, Elisabeth Martin, Marie Vanier, Isabelle Duluc, Isabelle Gross, Jean-Noël Freund, Claire Domon-Dell
• Journal: Nucleic acids research (Nucleic Acids Res) Vol. 40 Issue 8 Pg. 3456-69 (Apr 2012) ISSN: 1362-4962 [Electronic] England
• PMID: 22189105 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antigens, Nuclear
• CDX2 Transcription Factor
• CDX2 protein, human
• DNA-Binding Proteins
• Homeodomain Proteins
• Tumor Suppressor Proteins
• Etoposide
• DNA-Activated Protein Kinase
• Xrcc6 protein, human
• Ku Autoantigen

Topics

• Antigens, Nuclear (metabolism)
• CDX2 Transcription Factor
• Cell Line, Tumor
• Cell Survival
• Colonic Neoplasms (genetics, metabolism)
• DNA End-Joining Repair
• DNA-Activated Protein Kinase (metabolism)
• DNA-Binding Proteins (metabolism)
• Etoposide (toxicity)
• Homeodomain Proteins (chemistry, metabolism, physiology)
• Humans
• Ku Autoantigen
• Leukemia (genetics, metabolism)
• Protein Interaction Domains and Motifs
• Transcription, Genetic
• Tumor Suppressor Proteins (chemistry, metabolism, physiology)