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Identifying synthetic lethal interactions has emerged as a promising new therapeutic approach aimed at targeting cancer cells directly. Here, we used the yeast Saccharomyces cerevisiae as a simple eukaryotic model to screen for mutations resulting in a synthetic lethality with 5-amino-4-imidazole carboxamide ribonucleoside (AICAR) treatment. Indeed, AICAR has been reported to inhibit the proliferation of multiple cancer cell lines. Here, we found that loss of several histone-modifying enzymes, including Bre1 (histone H2B ubiquitination) and Set1 (histone H3 lysine 4 methylation), greatly enhanced AICAR inhibition on growth via the combined effects of both the drug and mutations on G1 cyclins. Our results point to AICAR impacting on Cln3 subcellular localization and at the Cln1 protein level, while the bre1 or set1 deletion affected CLN1 and CLN2 expression. As a consequence, AICAR and bre1/set1 deletions jointly affected all three G1 cyclins (Cln1, Cln2, and Cln3), leading to a condition known to result in synthetic lethality. Significantly, these chemo-genetic synthetic interactions were conserved in human HCT116 cells. Indeed, knock-down of RNF40, ASH2L, and KMT2D/MLL2 induced a highly significant increase in AICAR sensitivity. Given that KMT2D/MLL2 is mutated at high frequency in a variety of cancers, this synthetic lethal interaction has an interesting therapeutic potential.

The main objective of the CLAIM Project is to provide the knowledge base to support an effective CAP policy design in the direction of improved landscape management, particularly providing insights into the ability of landscape to contribute to the production of added value for society in rural areas. The CLAIM knowledge platform (KP) represents the interface between the research findings and policy-making contributing to further knowledge on the cause-effect relationships between landscape policy and management and the appearance of landscape (structure and elements) as well as the related ecosystem functionalities to the actual provision of ecosystem services, values and their application for regional competitiveness and social welfare. The theoretical framework of cause-effect-linkages is substantiated by empirical evidence from 25 individual research studies gathered in 9 different regions in the EU and Turkey. The specific challenge of the CLAIM-KP is the integrated presentation of thematically and methodologically heterogenic knowledge in one knowledge platform to enhance policy support in the field of agri-environmental and landscape management. The main addressee of the CLAIM-KP are: European policy maker in the fields of agri-environmental and landscape management policy and rural development, national and regional decision-makers at programming level as well as regional and local stakeholder and interest groups, who are involved in any kind of governance processes within landscape and rural development. The main output of the CLAIM-KP is qualitative knowledge about theoretical knowledge, but also information on empirical finding, which can be of qualitative and quantitative nature. The CLAIM-KP is accessible online under the following internet address http://project2.zalf.de/claimknowledgeplatform