Abstract IA07: New functions for histone modifying enzymes

Abstract

Abstract Histone modifying enzymes are important creating and maintaining epigenetic programs that regulate cell identity and growth. Mutations or abnormal expression of these proteins are associated with multiple cancers. Our lab uses genetic approaches to define the full spectrum of functions for these enzymes. For example, we have created a series of mutations in the mouse Gcn5 gene in order to define the functions of this histone acetyltransferase (HAT) in a mammalian system. Deletion of Gcn5 led to early embryonic death and to telomere dysfunction. Biochemical studies revealed that depletion of Gcn5 or ubiquitin specific protease 22 (Usp22), which is another bona fide component of the Gcn5-containing SAGA-type complex, increases the turnover of two shelterin proteins, TRF1 and POT1a (Atanassov, 2009). Our studies provided the first indication that Gcn5 and mammalian SAGA influence telomere maintenance and the first demonstration that SAGA affects protein stability. We are now defining the role of Gcn5 and SAGA in maintenance of pluripotency in ES cells and ES cell differentiation. Our data indicate that Gcn5 is an important cofactor for both Myc and E2F family transcription factors. We are also identifying additional USP22 protein substrates and are defining USP22 functions during mouse development. We have also discovered unexpected functions for the Set1 lysine methyltransferase, which is highly homologous with the MLL protein, during mitosis. We found that Set1 methylates kinetochore proteins, such as Dam1, in yeast, and we have determined that H2Bub is required in trans for methylation of this protein. This work provides the first example of cross talk between a histone modification and a modification in a non-histone protein, defining a new mode of “chromatin signaling.” Zhang K, Lin W, Latham JA, Riefler GM, Schumacher JM, Chan C, Tatchell K, Hawke DH, Kobayashi R, Dent SY. The Set1 methyltransferase opposes Ipl1 aurora kinase functions in chromosome segregation. Cell 122(5):723-34, 9/2005. PMCID: PMC1794220 Atanassov BS, Evrard YA, Multani AS, Zhang Z, Tora L, Devys D, Chang S, Dent SY. Gcn5 and SAGA Regulate Shelterin Protein Turnover and Telomere Maintenance. Mol Cell 35(3):352-364, 8/2009. PMCID: PMC2749492. Atanassov BS, Dent SY. USP22 regulates cell proliferation by deubiquitinating the transcriptional regulator FBP1. EMBO Rep 12(9):924-30, 9/2011. e-Pub 9/2011. PMCID: PMC3166460. Latham JA, Chosed RJ, Wang S, Dent SY. Chromatin signaling to kinetochores: Trans-regulation of Dam1 methylation by histone H2B ubiquitination. Cell 146(5):709-19, 9/2011. PMCID: PMC3168986. Citation Format: Sharon Y.R. Dent, Boyko Atanassov, Calley Hirsch, Evangelia Koutelou, John Latham. New functions for histone modifying enzymes. [abstract]. In: Proceedings of the AACR Special Conference on Chromatin and Epigenetics in Cancer; Jun 19-22, 2013; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2013;73(13 Suppl):Abstract nr IA07.