Aging and carcinogenesis coincide with the accumulation of DNA damage and mutations in stem and progenitor cells. Molecular mechanisms that influence responses of stem and progenitor cells to DNA damage remain to be delineated. Here, we show that niche positioning and Wnt signaling activity modulate the sensitivity of intestinal stem and progenitor cells (ISPCs) to DNA damage. ISPCs at the crypt bottom with high Wnt/β-catenin activity are more sensitive to DNA damage compared to ISPCs in position 4 with low Wnt activity. These differences are not induced by differences in cell cycle activity but relate to DNA damage-dependent activation of Wnt signaling, which in turn amplifies DNA damage checkpoint activation. The study shows that instructed enhancement of Wnt signaling increases radio-sensitivity of ISPCs, while inhibition of Wnt signaling decreases it. These results provide a proof of concept that cell intrinsic levels of Wnt signaling modulate the sensitivity of ISPCs to DNA damage and heterogeneity in Wnt activation in the stem cell niche contributes to the selection of ISPCs in the context of DNA damage.

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The authors state that it came to their attention that the figure legends of two figures were not sufficiently detailed in the original version of the manuscript.The figure Representative Western blots of cell lysates for the expression of phospho-p53 and cleaved caspase-3 (each n = 3; see Source Data for this figure). Samples from a single experiment were divided into identical portions and probed for phospho-p53 or cleaved casp3. The expression control of beta-actin was conducted on the second aliquot of the samples and was run in parallel on a separate gel.The corrections do not affect the original conclusions presented. We apologize for the lack of detail and any inconvenience it may have caused. Editorial NoteThese changes were based on the results of an investigation of the Leibniz Association. All authors agree with this correction.

These intriguing preliminary findings confirm IVS10-11G>A as a major mutation among Mediterranean mutations. For this population, exons 7 and 11 and adjacent introns, which carry more than 75% of the mutations, would have to be primarily screened. However, the other exons must be studied when either one or no mutations are found in the primary screening. The mutation spectrum in the patients with Azeri Turkish ethnic origin differed from that observed in patients from other Mediterranean countries and further defined the molecular heterogeneity of this disease.