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Mapping the Structure-Function Relationships of Disordered Oncogenic Transcription Factors Using Transcriptomic Analysis
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Negative Feedback Loop Mechanism between EAF1/2 and DBC1 in Regulating ELL Stability and Functions
Subham Basu1, Arijit Nandy1, Mahesh K Barad1
1Laboratory of Transcription Biology, Molecular Genetics Division, CSIR-Indian Institute of Chemical Biology, Kolkata, West Bengal, India.
Molecular and Cellular Biology
|August 29, 2022
Summary
ELL-associated factors 1 and 2 (EAF1/2) regulate ELL protein stability in vivo. They compete with HDAC3 and DBC1, forming feedback loops that maintain ELL levels for gene expression, with context-dependent pathway preference.
Area of Science:
- Molecular Biology
- Gene Regulation
- Protein Stability
Background:
- ELL-associated factors 1 and 2 (EAF1/2) enhance transcription in vitro, but in vivo roles are unclear.
- ELL protein's role in transcription is critical but its regulation is not fully understood.
Purpose of the Study:
- To elucidate the in vivo functions of EAF1/2 in regulating ELL protein stability.
- To investigate the interplay between EAF1/2, HDAC3, and DBC1 in maintaining ELL levels.
- To understand the context-dependent mechanisms controlling ELL protein homeostasis.
Main Methods:
- Investigated protein-protein interactions using competitive binding assays.
- Analyzed protein stability via acetylation and ubiquitylation assays.
- Utilized knockdown and expression studies to probe feedback loop mechanisms.
- Examined cellular responses to genotoxic stress and growth factors.
Main Results:
- EAF1/2 regulate ELL stability by competing with HDAC3, affecting acetylation and degradation.
- Negative feedback loops between DBC1 and EAF1/2 maintain overall ELL levels.
- TRIM28 mediates DBC1-induced EAF1/2 ubiquitylation and degradation.
- Mammalian cells employ EAF1-dependent pathways under genotoxic stress and DBC1-dependent pathways with growth factors.
Conclusions:
- EAF1/2, HDAC3, DBC1, and TRIM28 coordinate to regulate ELL protein levels for optimal gene expression.
- Negative feedback mechanisms involving EAF1/2 and DBC1 are crucial for ELL homeostasis.
- Mammalian cells exhibit distinct, context-dependent pathways for ELL maintenance.
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