Related Experiment Video
Updated: Aug 23, 2025
10:00
Assessment of Selective mRNA Translation in Mammalian Cells by Polysome Profiling
Published on: October 28, 2014
28.4K
Ribosome changes reprogram translation for chemosurvival in G0 leukemic cells.
Chandreyee Datta1, Samuel S Truesdell1, Keith Q Wu1
1Massachusetts General Hospital Cancer Center, Department of Medicine, Harvard Medical School, Boston, MA 02114, USA.
Science Advances
|October 28, 2022
Summary
The protein FXR1 helps leukemia cells survive chemotherapy by altering ribosomes and translation. Inhibiting FXR1 or its downstream effects reduces cancer cell survival.
Area of Science:
- Molecular Biology
- Cancer Biology
- Cellular Stress Response
Background:
- Quiescent leukemia cells exhibit resistance to chemotherapy.
- Translation regulation plays a critical role in cancer cell survival.
- The protein FXR1 is amplified in aggressive cancers.
Purpose of the Study:
- To investigate the role of FXR1 in chemoresistance of quiescent leukemic cells.
- To elucidate the mechanisms by which FXR1 promotes cancer cell survival.
- To identify potential therapeutic targets related to FXR1 in leukemia.
Main Methods:
- Analysis of FXR1 expression in quiescent and chemotherapy-treated leukemic cells.
- Assessment of translation rates and ribosomal composition upon FXR1 modulation.
- Investigation of the impact of FXR1 on ribosomal gene transcription and processing.
- Evaluation of the role of eIF2α kinases and phospho-eIF2α in FXR1-mediated chemosurvival.
- Testing the efficacy of inhibiting FXR1-related pathways in reducing chemosurvival.
Main Results:
- FXR1 is elevated in quiescent and chemo-treated leukemic cells, promoting chemosurvival.
- FXR1 depletion reduces global translation and alters ribosomal RNA (rRNA), small nucleolar RNA (snoRNA), and ribosomal protein (RP) profiles.
- FXR1 regulates the transcription and processing of ribosomal genes and snoRNAs.
- FXR1 overexpression leads to ribosome alterations that activate eIF2α kinases, increasing phospho-eIF2α.
- Elevated phospho-eIF2α enables selective translation of survival and immune-related genes.
- Inhibiting these pathways or phospho-eIF2α diminishes chemosurvival.
Conclusions:
- Elevated FXR1 in leukemia cells reprograms ribosomes, triggering stress signals that redirect translation for enhanced chemosurvival.
- FXR1's role in regulating translation and ribosome biogenesis is critical for chemoresistance.
- Targeting FXR1 or its downstream signaling pathways presents a promising therapeutic strategy for overcoming leukemia chemoresistance.
Related Concept Videos
02:24Ribosome Profiling
3.6K
Ribosome profiling or ribo-sequencing is a deep sequencing technique that produces a snapshot of active translation in a cell. It selectively sequences the mRNAs protected by ribosomes to get an insight into a cell’s translation landscape at any given point in time.
Applications of ribosome profiling
Ribosome profiling has many applications, including in vivo monitoring of translation inside a particular organ or tissue type and quantifying new protein synthesis levels.
The technique...
Applications of ribosome profiling
Ribosome profiling has many applications, including in vivo monitoring of translation inside a particular organ or tissue type and quantifying new protein synthesis levels.
The technique...
3.6K
02:28Leaky Scanning
5.2K
During most eukaryotic translation processes, the small 40S ribosome subunit scans an mRNA from its 5' end until it encounters the first start AUG codon. The large 60S ribosomal subunit then joins the smaller one to initiate protein synthesis. The location of the translation initiation is largely determined by the nucleotides near the start codon as there may be multiple translation initiation sites present on the mRNA. Marilyn Kozak discovered that the sequence RCCAUGG (where R...
5.2K
01:29Translational Regulation
75
Translational regulation in prokaryotes ensures efficient protein synthesis by controlling ribosome access to mRNA. This regulation is mediated by secondary RNA structures, including translational riboswitches, RNA thermometers, and small RNAs (sRNAs), which respond to intracellular and environmental signals to modulate gene expression.Translational RiboswitchesRiboswitches in the leader region of mRNAs can regulate translation by altering the accessibility of the Shine-Dalgarno (SD) sequence,...
75
01:44Termination of Translation
25.6K
The large ribosomal subunit has several important structures essential to translation. These include the peptidyl transferase center (PTC) - which is the site where the peptide bond is formed - and a large, internal, water-filled tube through which the nascent polypeptide moves. This latter structure is called the Peptide Exit Tunnel, and it begins at the PTC and spans the body of the large ribosomal subunit. During translation, as the nascent polypeptide chain is synthesized, it passes through...
25.6K
02:55The Nucleolus
9.0K
The nucleolus is the most prominent substructure of the nucleus. When it was first discovered, it was considered to be an isolated organelle that forms fibrils and granules. In 1931, the relationship between the nucleolus and chromosomes was first described by Heitz. He observed that the appearance and size of nucleolus varies depending on the stage of the cell cycle. He also noticed constricted regions on different chromosomes clustered together at definite cell cycle stages. These regions,...
9.0K
02:07Improving Translational Accuracy
11.8K
Base complementarity between the three base pairs of mRNA codon and the tRNA anticodon is not a failsafe mechanism. Inaccuracies can range from a single mismatch to no correct base pairing at all. The free energy difference between the correct and nearly correct base pairs can be as small as 3 kcal/ mol. With complementarity being the only proofreading step, the estimated error frequency would be one wrong amino acid in every 100 amino acids incorporated. However, error frequencies observed in...
11.8K