Marc Brehme

Publications

• 9.43

  Impact points

  Charting the molecular network of the drug target Bcr-Abl.

  Marc Brehme, Oliver Hantschel, Jacques Colinge, Ines Kaupe, Melanie Planyavsky, Thomas Köcher, Karl Mechtler, Keiryn L Bennett, Giulio Superti-Furga

  Proceedings of the National Academy of Sciences of the United States of America. 05/2009;

  The tyrosine kinase Bcr-Abl causes chronic myeloid leukemia and is the cognate target of tyrosine kinase inhibitors like imatinib. We have charted the protein-protein interaction network of Bcr-Abl by a 2-pronged approach. Using a monoclonal antibody we have first purified endogenous Bcr-Abl protein... [more] The tyrosine kinase Bcr-Abl causes chronic myeloid leukemia and is the cognate target of tyrosine kinase inhibitors like imatinib. We have charted the protein-protein interaction network of Bcr-Abl by a 2-pronged approach. Using a monoclonal antibody we have first purified endogenous Bcr-Abl protein complexes from the CML K562 cell line and characterized the set of most tightly-associated interactors by MS. Nine interactors were subsequently subjected to tandem affinity purifications/MS analysis to obtain a molecular interaction network of some hundred cellular proteins. The resulting network revealed a high degree of interconnection of 7 "core" components around Bcr-Abl (Grb2, Shc1, Crk-I, c-Cbl, p85, Sts-1, and SHIP-2), and their links to different signaling pathways. Quantitative proteomics analysis showed that tyrosine kinase inhibitors lead to a disruption of this network. Certain components still appear to interact with Bcr-Abl in a phosphotyrosine-independent manner. We propose that Bcr-Abl and other drug targets, rather than being considered as single polypeptides, can be considered as complex protein assemblies that remodel upon drug action.

• Functional Proteomics of Bcr-Abl Signaling

  Marc Brehme

  03/2009

  Degree: Ph.D

  Supervisor: Prof. Giulio Superti-Furga
• 2.00

  Impact points

  Intercell - accelerating innovation.

  Marc Brehme

  New biotechnology. 02/2009; 25(4):181-4.

  An interview with Alexander von Gabain, CSO of Intercell, one of the leading companies in the area of vaccine development.
• 12.08

  Impact points

  A core transcriptional network for early mesoderm development in Drosophila melanogaster.

  Thomas Sandmann, Charles Girardot, Marc Brehme, Waraporn Tongprasit, Viktor Stolc, Eileen E M Furlong

  Genes & development. 03/2007; 21(4):436-49.

  Embryogenesis is controlled by large gene-regulatory networks, which generate spatially and temporally refined patterns of gene expression. Here, we report the characteristics of the regulatory network orchestrating early mesodermal development in the fruitfly Drosophila, where the transcription fac... [more] Embryogenesis is controlled by large gene-regulatory networks, which generate spatially and temporally refined patterns of gene expression. Here, we report the characteristics of the regulatory network orchestrating early mesodermal development in the fruitfly Drosophila, where the transcription factor Twist is both necessary and sufficient to drive development. Through the integration of chromatin immunoprecipitation followed by microarray analysis (ChIP-on-chip) experiments during discrete time periods with computational approaches, we identified >2000 Twist-bound cis-regulatory modules (CRMs) and almost 500 direct target genes. Unexpectedly, Twist regulates an almost complete cassette of genes required for cell proliferation in addition to genes essential for morophogenesis and cell migration. Twist targets almost 25% of all annotated Drosophila transcription factors, which may represent the entire set of regulators necessary for the early development of this system. By combining in vivo binding data from Twist, Mef2, Tinman, and Dorsal we have constructed an initial transcriptional network of early mesoderm development. The network topology reveals extensive combinatorial binding, feed-forward regulation, and complex logical outputs as prevalent features. In addition to binary activation and repression, we suggest that Twist binds to almost all mesodermal CRMs to provide the competence to integrate inputs from more specialized transcription factors.
• 31.15

  Impact points

  A genome-wide screen identifies the evolutionarily conserved KEOPS complex as a telomere regulator.

  Michael Downey, Rebecca Houlsworth, Laura Maringele, Adrienne Rollie, Marc Brehme, Sarah Galicia, Sandrine Guillard, Melanie Partington, Mikhajlo K Zubko, Nevan J Krogan, Andrew Emili, Jack F Greenblatt, Lea Harrington, David Lydall, Daniel Durocher

  Cell. 04/2006; 124(6):1155-68.

  Telomere capping is the essential function of telomeres. To identify new genes involved in telomere capping, we carried out a genome-wide screen in Saccharomyces cerevisiae for suppressors of cdc13-1, an allele of the telomere-capping protein Cdc13. We report the identification of five novel suppres... [more] Telomere capping is the essential function of telomeres. To identify new genes involved in telomere capping, we carried out a genome-wide screen in Saccharomyces cerevisiae for suppressors of cdc13-1, an allele of the telomere-capping protein Cdc13. We report the identification of five novel suppressors, including the previously uncharacterized gene YML036W, which we name CGI121. Cgi121 is part of a conserved protein complex -- the KEOPS complex -- containing the protein kinase Bud32, the putative peptidase Kae1, and the uncharacterized protein Gon7. Deletion of CGI121 suppresses cdc13-1 via the dramatic reduction in ssDNA levels that accumulate in cdc13-1 cgi121 mutants. Deletion of BUD32 or other KEOPS components leads to short telomeres and a failure to add telomeres de novo to DNA double-strand breaks. Our results therefore indicate that the KEOPS complex promotes both telomere uncapping and telomere elongation.