The MLL fusion partner AF10 binds GAS41, a protein that interacts with the human SWI/SNF complex

Abstract

The AF10 gene encodes a putative transcription factor containing an N-terminal LAP/PHD zinc finger motif, a functional nuclear localization signal, an AT-hook domain, and a leucine zipper toward the C-terminus. AF10 is involved in 2 distinct chromosomal translocations associated with hematologic malignancy. The chimeric fusion proteins MLL/AF10 and CALM/AF10, resulting from the t(10; 11)(p12;q23) and the t(10;11)(p12;q14), respectively, consistently retain the leucine zipper motif of AF10. This part of the C-terminal region was used as bait in a yeast 2 hybrid screening of a testis complementary DNA library. The leucine zipper interacted with GAS41, a protein previously identified as the product of an amplified gene in a glioblastoma. GAS41 shows significant homology to the Saccharomyces cerevisiae protein ANC1 and to the human MLL fusion partners AF9 and ENL. The interaction was confirmed in vivo. Furthermore, the study showed by coimmunoprecipitation that GAS41 in IntroductionThe disruption of the human homologue of the Drosophila Trithorax (trx) gene, MLL on 11q23 1-4 by chromosomal translocations is a frequent event in human acute leukemia. These translocations, leading to the juxtaposition of genetic elements and formation of MLL fusion genes, occur in approximately 5% to 10% of human acute leukemias, but with a higher frequency in infant leukemias 5 and secondary leukemias. 6 Although the full biological function of MLL is uncertain, it is known to act as a positive regulator of HOX gene expression in development. 7,8 Currently, 20 different translocations affecting the MLL gene have been molecularly cloned and the partner genes identified. 9 Significantly, all such translocations result in in-frame fusions at the messenger RNA level, and, therefore, the rearrangements result in the production of chimeric proteins in which the N-terminus of MLL is consistently fused to the C-terminus encoded by the partner gene. [10][11][12] Because such a diverse group of proteins can be fused to MLL, the role of the fusion proteins in leukemogenesis remains obscure. 13 Although most of the fusion partners are structurally and functionally unrelated to each other, 14 a number are involved in transcriptional regulation. For example, ENL, AF9, and AF4 activate transcription from synthetic reporter genes in vivo. [15][16][17][18][19][20] The AF10 gene is one of the few MLL partner genes to be independently rearranged with a third gene in leukemia, the CALM gene in the t(10;11)(p12;q14) translocation. 21 AF10 complementary DNA (cDNA) encodes a 1084-aa protein, a member of a family of proteins including MLL, all carrying a conserved LAP/PHD finger domain. 22,23 There is also a putative AT-hook motif, 24 a bipartite nuclear localization signal, a leucine zipper domain, and a glutamine-rich region at the C-terminus. The latter is not present in all isoforms, as a result of alternative splicing. 25,26 Although different breakpoints have been described for AF10, the resultant fusion protein in both products consistently loses the...

NuMA Influences Higher Order Chromatin Organization in Human Mammary Epithelium

“…Another P. C. Abad et al explanation for the effect of NuMA on chromatin structure may be linked to the location of NuMA in the chromatin compartment. In this compartment, NuMA could interact with the putative transcription factor GAS41 (Harborth et al, 2000), a protein shown to bind the chromatin remodeling complex component INI1 (Debernardi et al, 2002). In addition, chromatin-remodeling complexes have been shown to contain actin-related proteins.…”

MLL fusion partners AF4 and AF9 interact at subnuclear foci

“…61 In addition, the MLL partner AF10 interacts with the AF9 family member GAS41 which in turn interacts with INI1, also called SNF5. 62 In yeast, SNF5 also interacts with the AF9 family member TGF3. 63 CBP interacts with a newly discovered member of the SWI/SNF complex, SRCAP.…”

Linking the epigenetic ‘language’ of covalent histone modifications to cancer

“…t(11;19), associate and cooperate with SWI/ SNF complexes to activate transcription of the Hoxa7 promoter (Nie et al, 2003). Fusion of MLL to AF10, t(10;11)(p12;23), creates a protein that could interact with GAS41, a member of the basal transcription factor complexes TFIID and TFIIF, and an interacting component of SWI/SNF, and potentially activate Hox gene expression by aberrant chromatin remodelling (Debernardi et al, 2002). Intriguingly, dimerisation of the truncation Figure 1A, are integrated into nucleosomes by a yet not understood mechanism.…”