Related Experiment Video

Updated: Jun 11, 2025

Delivery of Modified mRNA in a Myocardial Infarction Mouse Model
06:03

Delivery of Modified mRNA in a Myocardial Infarction Mouse Model

Published on: June 11, 2020

9.0K

Programmed ribosomal frameshifting during PLEKHM2 mRNA decoding generates a constitutively active proteoform that

Gary Loughran1, Raffaella De Pace2, Ningyu Ding3

  • 1School of Biochemistry and Cell Biology, University College Cork, Cork, Ireland.

Biorxiv : the Preprint Server for Biology
|October 7, 2024
PubMed

Insights

Scientists discovered programmed ribosomal frameshifting in the human gene PLEKHM2, a rare event in nuclear genes. This frameshifting is crucial for normal heart cell function.

Area of Science:

  • Molecular Biology
  • Genetics
  • Cell Biology

Background:

  • Programmed ribosomal frameshifting is a known mechanism, primarily in viruses, for altering protein synthesis.
  • Conserved frameshifting events in nuclear-encoded genes are rare and often debated.
  • The gene PLEKHM2 plays a role in cellular processes, but its full regulatory mechanisms are not completely understood.

Purpose of the Study:

  • To investigate the phenomenon of programmed ribosomal frameshifting in the human gene PLEKHM2.
  • To characterize the mechanism and functional significance of this frameshifting event.
  • To determine the role of frameshifting in PLEKHM2's function and cellular localization.

Main Methods:

  • Analysis of mRNA sequences and ribosome behavior during translation of PLEKHM2.
  • Site-directed mutagenesis to identify the frameshifting signal.
  • Cellular localization studies using microscopy.
  • Functional assays in PLEKHM2-knockout cardiomyocytes.

Main Results:

  • A +1 programmed ribosomal frameshifting event was identified in the human PLEKHM2 gene at the conserved UCC_UUU_CGG sequence.
  • The frameshift generates a novel C-terminal domain that forms an alpha-helix, relieving autoinhibition of PLEKHM2.
  • Frameshifted PLEKHM2 associates with kinesin-1 for transport to cellular tips, independent of ARL8.
  • Restoration of both canonical and frameshifted PLEKHM2 proteins is required to rescue contractile function in knockout cardiomyocytes.

Conclusions:

  • Programmed ribosomal frameshifting is essential for PLEKHM2 function and normal cardiac activity.
  • This finding expands the known repertoire of frameshifting mechanisms in nuclear-encoded genes.
  • The frameshift-dependent regulation of PLEKHM2 impacts its localization and cellular function, particularly in cardiomyocytes.

More Related Videos

De novo Identification of Actively Translated Open Reading Frames with Ribosome Profiling Data08:23

De novo Identification of Actively Translated Open Reading Frames with Ribosome Profiling Data

Published on: February 18, 2022

3.5K
Dual-Dye Optical Mapping of Hearts from RyR2R2474S Knock-In Mice of Catecholaminergic Polymorphic Ventricular Tachycardia09:36

Dual-Dye Optical Mapping of Hearts from RyR2R2474S Knock-In Mice of Catecholaminergic Polymorphic Ventricular Tachycardia

Published on: December 22, 2023

1.1K

Related Concept Videos

Nonsense-mediated mRNA Decay02:27

Nonsense-mediated mRNA Decay

The Upf proteins that carry out nonsense-mediated decay (NMD) are found in all eukaryotic organisms, including humans. Each protein has an individual role, but they need to work in collaboration. Upf1 is an ATP-dependent RNA helicase that unwinds the RNA helix. Because Upf1 can unwind any RNA, Upf2 and Upf3 are required to help Upf1 discriminate between nonsense and normal mRNAs.
Usually, Upf3 binds to an Exon Junction Complex (EJC) at mRNA splice sites. If a ribosome fully translates the mRNA,...
10.6K
Ribosome Profiling02:24

Ribosome Profiling

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...
3.5K
Leaky Scanning02:28

Leaky Scanning

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...
5.1K
Translation01:31

Translation

Translation is the process of synthesizing proteins from the genetic information carried by messenger RNA (mRNA). Following transcription, it constitutes the final step in the expression of genes. This process is carried out by ribosomes, complexes of protein and specialized RNA molecules. Ribosomes, transfer RNA (tRNA), and other proteins produce a chain of amino acids—the polypeptide—as the end product of translation.
Translation Produces the Building Blocks of Life
Proteins are...
14.6K
Regulated mRNA Transport02:22

Regulated mRNA Transport

In eukaryotes, transcription and translation are compartmentalized; an mRNA is first synthesized in the nucleus and then selectively transported to the cytoplasm for protein synthesis. Before transport, a pre-mRNA undergoes several steps of post-transcriptional modifications including splicing, 5' capping, and the addition of a poly-adenine tail. Various proteins bind to the pre-mRNA during these modifications. The mRNA transport takes place with the help of multiple proteins playing...
6.3K
Ribosomal RNA Synthesis02:53

Ribosomal RNA Synthesis

Ribosome synthesis is a highly complex and coordinated process involving more than 200 assembly factors. The synthesis and processing of ribosomal components occurs not only in the nucleolus but also in the nucleoplasm and the cytoplasm of eukaryotic cells.
Ribosome biogenesis begins with the synthesis of 5S and 45S pre-rRNAs by distinct RNA polymerases. The primary transcripts are extensively processed and modified before they are bound and folded by ribosomal proteins and assembly factors,...
13.1K