Nipped-A, the Tra1/TRRAP Subunit of the Drosophila SAGA and Tip60 Complexes, Has Multiple Roles in Notch Signaling during Wing Development

Abstract

The Notch receptor controls development by activating transcription of specific target genes in response to extracellular signals. The factors that control assembly of the Notch activator complex on target genes and its ability to activate transcription are not fully known. Here we show, through genetic and molecular analysis, that the Drosophila Nipped-A protein is required for activity of Notch and its coactivator protein, mastermind, during wing development. Nipped-A and mastermind also colocalize extensively on salivary gland polytene chromosomes, and reducing Nipped-A activity decreases mastermind binding. Nipped-A is the fly homologue of the yeast Tra1 and human TRRAP proteins and is a key component of both the SAGA and Tip60 (NuA4) chromatin-modifying complexes. We find that, like Nipped-A, the Ada2b component of SAGA and the domino subunit of Tip60 are also required for mastermind function during wing development. Based on these results, we propose that Nipped-A, through the action of the SAGA and Tip60 complexes, facilitates assembly of the Notch activator complex and target gene transcription.

Nipped-A regulates intestinal stem cell proliferation in Drosophila

“…Among the differentially expressed genes, Nipped-A transcripts were significantly upregulated in aged ISCs. The only previous study exploring the function of Nipped-A in Drosophila showed that it positively regulates N signaling in wing development (Gause et al, 2006). Interestingly, our findings do not support a role for Nipped-A in promoting N signaling in midgut ISCs as knocking down Nipped-A did not phenocopy the N loss-offunction phenotypes.…”

“…The function and biological importance of Drosophila Nipped-A is largely uncharacterized on a tissue-and cell-specific level. So far it has only been shown that Nipped-A promotes N signaling activity in wing development (Gause et al, 2006).…”

“…However, to date, only few studies have investigated chromatin modifiers in the process of regulating ISC behavior in Drosophila (Amcheslavsky et al, 2014;Buszczak et al, 2009;Jin et al, 2013;Ma et al, 2013;Zeng et al, 2013). Nipped-A is the Drosophila homolog of mammalian transformation/transcription domain-associated protein (TRRAP) and yeast Tra1 and is an important subunit of histone acetyltransferase (HAT) complexes such as SAGA and Tip60 (Gause et al, 2006;Kusch et al, 2003;Murr et al, 2007). TRRAP/ Tra1 is thought to function mainly as a scaffold for facilitating protein-protein interactions and recruiting various regulatory complexes to chromatin (Murr et al, 2007).…”

Orchestration of chromatin-based processes: mind the TRRAP

“…Similarly, loss of function mutations in trr1 gene of C. elegans cause developmental defect (Ceol and Horvitz, 2004). In addition, a genetic study in Drosophila showed that Nipped-A plays a role in Notch signaling and wing development (Gause et al, 2006). These studies provide evidence that TRRAP/Tra1/trr1/ Nipped-A plays an essential role in development, although its involvement in different pathways during embryogenesis remains to be elucidated.…”

Notch signaling at a glance

“…Here, the RAM domain of NICD allows its interaction with CSL, which facilitates the binding of MAM at the interface between the ANK domain of NICD and CSL (Choi et al, 2012). This complex further recruits coactivators, such as histone acetyltransferases (CBP/p300) and chromatin remodeling complexes, which mediate the transcription of Notch target genes (Wallberg et al, 2002;Kadam and Emerson, 2003;Gause et al, 2006). Kinases, such as glycogen synthase kinase 3b (GSK3b), granulocyte colony stimulating factor (G-CSF) and cyclin C/ cyclin-dependent kinase-8 (CDK8), have been shown to phosphorylate NICD, which is thought to be important for the stability of NICD and hence its activity (Inglés-Esteve et al, 2001;Espinosa et al, 2003;Fryer et al, 2004).…”