INSERM, U682, F-67200 Strasbourg, France.
Nucleic Acids Res. 2012 Apr;40(8):3456-69. doi: 10.1093/nar/gkr1242. Epub 2011 Dec 20.
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.
Cdx2 是同源盒基因簇的一个基因，编码一个同源域转录因子，在胚胎发育和成人肠道稳态中发挥多种作用。虽然 Cdx2 在肠道中发挥肿瘤抑制功能，但它在急性白血病中的异常异位表达与致癌功能有关。为了试图理解这种双重性，我们假设 Cdx2 可能在这两种组织中与不同的蛋白质伴侣相互作用，并通过串联亲和纯化实验来鉴定它们。我们在这里表明，Cdx2 通过其同源域特异性地与肠道细胞中的 Ku 异二聚体相互作用，但不在白血病细胞中相互作用。Ku 蛋白不影响 Cdx2 的转录活性。然而，Cdx2 抑制体内和体外肠道细胞中 Ku 蛋白介导的 DNA 修复活性。尽管 Cdx2 不影响 Ku 蛋白和 DNA-PKcs 进入 DNA 修复复合物的募集，但它抑制了 DNA-PKcs 的活性。因此，我们在这里报道了 Cdx2 的一个新功能，作为 DNA 修复机制的抑制剂，这可能有助于其在肠道中特有的肿瘤抑制功能。
