In Science this week, researchers at the Rockefeller University report on the role of Rap1, a conserved subunit of shelterin, which is an essential telomeric protein complex that prevents damage to DNA. In removing Rap1 from mouse telomeres via gene deletions or by replacing TRF2 with a mutant that doesn't bind Rap1, the team found that it is critical for the repression of homology-directed repair, which can alter telomere length. "The data reveal that HDR at telomeres can take place in the absence of DNA damage foci and underscore the functional compartmentalization within shelterin," the researchers write.
Meanwhile, in Science Signaling, researchers in Japan and the UK say that the regulation of Zap70 expression during thymocyte development enables the temporal separation of CD4 and CD8 repertoire selection at different signaling thresholds. They developed a transgenic mouse that expressed a tetracycline-inducible gene encoding Zap70; in wild-type mice, expression of endogenous Zap70 progressively increases and expression of the Zap70 protein determined the sensitivity of cells to stimulations of the T cell antigen receptor. "This temporal gradient in the amount of Zap70 protein enabled the selection of CD4+ and CD8+ repertoires in separate temporal windows and at different TCR signaling thresholds, thereby facilitating discrimination of distinct positive selection signals in these lineages," they write.
In an advance, online publication of Science, researchers in Switzerland write that "by altering the tumor microenvironment, CCL21-secreting tumors shift the host immune response from immunogenic to tolerogenic, thereby facilitating tumor progression." Many cancers secrete the chemoattractant CCL21, they say, adding that CCL21 expression by melanoma tumors in mice is associated with an immunotolerant microenvironment. Conversely, CCL21-deficent tumors induce antigen-specific immunity.
And in a commentary in Science Translational Medicine this week, Ian Mills, from Cancer Research UK, and Richard Sykes, from NHS London, write that deCODE Genetics' filing for bankruptcy in the fall "highlights the commercial risks of translational research." The authors say that neither "a purely corporate nor purely academic model" is the best fit for this type of work. "Instead, we suggest that the private sector undertake the high-throughput elements of translational research, while the public sector and governments assume the role of providing long-term funding to develop gifted scientists with the confidence to attempt to use genetic data as a stepping stone to a truly mechanistic understanding of complex disease," they conclude.