The senescence of mammalian cells is characterized by a proliferative arrest in response to stress and the expression of an inflammatory phenotype. Here we show that histone H2A.J, a poorly studied H2A variant found only in mammals, accumulates in human fibroblasts in senescence with persistent DNA damage. H2A.J also accumulates in mice with aging in a tissue-specific manner and in human skin. Knock-down of H2A.J inhibits the expression of inflammatory genes that contribute to the senescent-associated secretory phenotype (SASP), and over expression of H2A.J increases the expression of some of these genes in proliferating cells. H2A.J accumulation may thus promote the signalling of senescent cells to the immune system, and it may contribute to chronic inflammation and the development of aging-associated diseases.

The discovery of new chemical reactions is a long-standing goal of organic chemists. For decades, synthetic problems motivated the development of new methodologies to continuously expand the reaction toolkit in organic synthesis. As alternatives to purely rational approaches, strategies that offer more room for serendipity have recently emerged. In these approaches, the discovery is a result of the systematic exploration of a large number of chemical reactions through the use of robust high-throughput screening methods based either on mass spectrometry techniques [1] or on DNA technologies. [2] Although this strategy was already proven to be efficient with the discovery of several new interesting reactions, [3] this does not guarantee the potential impact of the discovered reactions. A more powerful approach would be the increase of the level of selection in a manner that only powerful reliable reactions are discovered. Such a highly demanding selection should therefore be based not only on reaction efficiencies, but also on other parameters that would ensure the usefulness of the discovered reaction. In 2001, K. B. Sharpless introduced the concept of "click chemistry", which has been widely and successfully applied since then, and listed a series of important criteria that may influence the extent and the impact of a chemical reaction. [4] Among them, chemoselectivity, simplicity of reaction conditions, and high efficiency, even in complex media, are probably the most important ones. This can be highlighted by the startling number of applications in organic synthesis, materials science, and biotechnology of the copper-catalyzed alkyne-azide cycloaddition reaction (CuAAC), which is one of the most powerful click reactions described to date. [5] Herein, we disclose an approach to accelerate the discovery of such important chemical reactions through the use of an immunoassay technique. As we previously described, [6] sandwich immunoassays can be successfully applied to monitor cross-coupling reactions by connecting small-molecule tags to chemically reactive groups. Products of bond-forming coupling reactions can then be specifically detected by two specific antitag monoclonal antibodies (mAbs) using standard ELISA techniques: one mAb captures the doubletagged coupling product on a solid phase and a second acts as a detector. We recently showed that the throughput of this adapted immunoassay (typically around 1000 analyses per day and person) allows the fast identification of new reactions among thousands of combinations of reactive functions and catalysts. [7] One crucial advantage of this screening method relies on the high specificity of mAbs, permitting the precise and sensitive quantification of the double-tagged crosscoupling products in complex mixtures without work-up. Here, we decided to fully exploit this advantage by designing a series of successive screening in order to identify new, efficient, chemoselective, and biocompatible [3+2] cycloaddition reactions. Our approach (Figure 1) involves three mai...