Abstract
Among all of the Super Elongation Complex (SEC) components, ELL1 (also known as ELL) is the only bona fide elongation factor that directly stimulates transcription elongation by RNA polymerase II. However, the mechanism(s) of functional regulation of ELL1 (referred to as ELL hereafter), through its stabilization, is completely unknown. Here, we report a function of human DBC1 in regulating ELL stability involving HDAC3, p300, and Siah1. Mechanistically, we show that p300-mediated site-specific acetylation increases, whereas HDAC3-mediated deacetylation decreases, ELL stability through polyubiquitylation by the E3 ubiquitin ligase Siah1. DBC1 competes with HDAC3 for the same binding sites on ELL and thus increases its acetylation and stability. Knockdown of DBC1 reduces ELL levels and expression of a significant number of genes, including those involved in glucose metabolism. Consistently, Type 2 diabetes patient-derived peripheral blood mononuclear cells show reduced expression of DBC1 and ELL and associated key target genes required for glucose homeostasis. Thus, we describe a pathway of regulating stability and functions of key elongation factor ELL for expression of diverse sets of genes, including ones that are linked to Type 2 diabetes pathogenesis.
Highlights
During the last few decades, studies in the field of transcriptional regulation were focused on detailed understanding of factors involved, and their role, in regulation of the initiation step
We describe an important pathway in regulating the stability, and function, of a key Super Elongation Complex (SEC) component, that is, ELL
Our results show a multilayered regulation involving Deleted in Breast Cancer 1 (DBC1), acetyltransferase p300, deacetylase HDAC3, and an E3 ubiquitin ligase, Siah1
Summary
During the last few decades, studies in the field of transcriptional regulation were focused on detailed understanding of factors involved, and their role, in regulation of the initiation step. Besides SEC, ELL associates with EAF1, KIAA0947 (aka ICE1), and NARG2 (aka ICE2) to form Little Elongation Complex (LEC) that functions in regulating small nuclear RNA gene transcription by Pol II as well as in the recruitment of TFIIH during transcription-coupled DNA repair [11,12,13]. Mechanisms of ELL2 degradation by the E3 ubiquitin ligase, Siah, have been described by two earlier studies [14, 15], regulation of ELL function through its stabilization is completely unknown. In this regard, we were intrigued by the strong association of Deleted in Breast Cancer 1 (DBC1) in our ELL.com mass spectrometric analysis [2] and SI Appendix, Fig. S1A. We describe a role of DBC1 in regulation of ELL stability, and its function(s) within mammalian cells that
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