Distinct and Non-Redundant Functions of the Human mRNA Decapping Cofactor Paralogs DCP1a and DCP1b

Core Concepts

DCP1a and DCP1b, the two human paralogs of the mRNA decapping cofactor DCP1, have distinct and non-redundant roles in regulating the integrity and specificity of the mRNA decapping complex.

Abstract

The content examines the functional differences between the two human paralogs of the mRNA decapping cofactor DCP1, DCP1a and DCP1b. Key findings:

DCP1a, but not DCP1b, is essential for maintaining the interaction between the decapping enzyme DCP2 and the decapping enhancer proteins EDC4 and EDC3. This suggests DCP1a plays a critical role in decapping complex assembly.

Proteomic analysis of the DDX6 interactome revealed that DCP1a loss decreases interactions with other RNA regulatory proteins, while DCP1b loss specifically impacts interactions with translation initiation factors.

DCP1a and DCP1b have largely non-overlapping interactomes, with DCP1a associating more with proteins involved in transcription and chromatin regulation, and DCP1b associating more with proteins involved in translation.

SLAM-seq analysis showed that loss of DCP1a or DCP1b impacts the half-lives of distinct sets of mRNAs, with DCP1a regulating mRNAs involved in immunity and transcription, and DCP1b regulating mRNAs involved in lymphocyte/leukocyte differentiation.

Despite the impact on mRNA half-lives, the effects on protein levels are buffered, suggesting the decapping complex plays a role in transcript buffering to maintain homeostasis.

Overall, the data provides the first functional dissection of the distinct roles of the DCP1 paralogs in human cells, highlighting their non-redundant functions in regulating mRNA decapping, stability, and ultimately gene expression.

Stats

"Decapping complex members and exoribonucleases are among the proteins localized to PBs, leading to a model in which PBs are also a site of mRNA decapping and subsequent degradation."
"DCP2 has low basal decapping activity in vitro, and its enzymatic activity is greatly enhanced by its interaction with its main decapping activator DCP1."
"DCP1a and DCP1b can both homo- and hetero-trimerize via their TD domain (TD), and it is the trimeric form of DCP1a/DCP1b that is found with DCP2 in the decapping complex."

Quotes

"DCP1a is essential for decapping complex assembly and for interactions between the decapping complex and mRNA cap binding proteins."
"In contrast, DCP1b is essential for decapping complex interactions with the translational machinery."
"DCP1a controls mRNAs that encode proteins with a role in adaptive immunity and transcription, while a separate group of DCP1b-dependent mRNAs also plays a role in transcription."

Key Insights Distilled From

Non-redundant roles for the human mRNA decapping cofactor paralogs DCP1a and DCP1b

by Vukovic,I., ... at www.biorxiv.org 10-19-2023

https://www.biorxiv.org/content/10.1101/2023.10.19.563039v1

Deeper Inquiries

What are the potential physiological or developmental contexts in which the distinct functions of DCP1a and DCP1b become most relevant?

The distinct functions of DCP1a and DCP1b are likely to be most relevant in contexts where precise regulation of gene expression is crucial for physiological or developmental processes. For example, during embryonic development, where specific genes need to be tightly controlled to ensure proper differentiation and organogenesis, the unique roles of DCP1a and DCP1b in mRNA turnover and decapping complex assembly could play a critical role. Additionally, in tissues with high rates of protein synthesis and turnover, such as muscle tissue or the immune system, the differential interactions of DCP1a and DCP1b with the translational machinery could be essential for maintaining homeostasis and responding to external stimuli.

How might the differential interactions of DCP1a and DCP1b with the transcriptional and translational machinery contribute to coordinated regulation of gene expression programs?

The differential interactions of DCP1a and DCP1b with the transcriptional and translational machinery could contribute to coordinated regulation of gene expression programs by providing a level of specificity and fine-tuning to the decapping complex. DCP1a, with its role in maintaining decapping complex integrity and interactions with RNA cap binding proteins, may be more involved in regulating mRNA stability and turnover of specific subsets of mRNAs. On the other hand, DCP1b, which is essential for interactions with the translational machinery, could play a key role in modulating translation efficiency and protein synthesis of distinct mRNA populations. This differential regulation allows for precise control over gene expression programs, ensuring that the right genes are expressed at the right time and in the right amounts.

Could the transcript buffering role of the decapping complex be leveraged for therapeutic applications, such as stabilizing mRNAs encoding beneficial proteins or destabilizing mRNAs encoding pathogenic proteins?

The transcript buffering role of the decapping complex presents an intriguing opportunity for therapeutic applications. By modulating the stability of specific mRNAs, it may be possible to stabilize mRNAs encoding beneficial proteins, such as growth factors or tumor suppressors, to enhance their expression and therapeutic effects. Conversely, destabilizing mRNAs encoding pathogenic proteins, such as oncogenes or inflammatory mediators, could be a strategy to reduce their expression and mitigate disease progression. Targeting DCP1a or DCP1b, or their interacting partners, could offer a novel approach to fine-tune gene expression profiles for therapeutic purposes, opening up new avenues for precision medicine and targeted therapies.