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Session 5.2: Gamble
1. The Role of macroH2A Alternative Splicing in Regulating Chromatin Structure and Function during Cancer and Senescence Matthew Gamble AECC Advances Meeting May 5th 2010
2. What is macroH2A? Histone 1 131 Canonical H2A N- -C 65% identity Macro Linker 1 122 368 160 MacroH2A1 -C N- Basic α-satellite DNA (1U35) α-satellite DNA (1AOI) M. musculusH3, H4, H2B (1U35) X. laevisH3, H4, H2B (1AOI) H. sapiensmacroH2A (1U35) X. laevisH2A (1AOI) Chakravarthy (2005) Mol Cell Biol 25:7616 Costanzi, Pehrson1998 Nature 393:599
3. What Factors Lead to the Deposition of macroH2A? ? What Effects does macroH2A have on Chromatin Structure and Gene Expression?
18. Summary / Working Model * RAS/RAF Cancer Normal MEK PARP-1 ERK PARP-1 PELP1 PELP1 1.2 1.2 1.1 1.2 Proliferation Growth Suppression Senescence
19. Is macroH2A1.1 status an additional predictor of PARP inhibitor efficacy? DNA Damage ERK PARP-1 PARP-1 PELP1 Nucleotide Excision Repair Homologous Repair 1.1 1.2 BRCA1 BRCA2 Growth Suppression Senescence Cancer Cell Survival
20. Acknowledgements Gamble Lab Einstein Hongshan Chen Susan Horwitz (Mol Pharm) Hailey McDaid Laura Klein Charlie Rubin (Mol Pharm) Art Skoultchi (Cell Bio) John Greally (Genetics) Robert Gallagher (Medicine) AmitVerma (Medicine and DMB) Ulrich Steidl (Cell Bio) Joe Sparano (Medicine, Oncology) Leonid Novikov W. Lee Kraus (Cornell, Ithaca) Kristine Frizzell Raga Krishnakumar Christine Yang Eugene Park Tong Zhang Sidney Kimmel Foundation for Cancer Research