The mechanism underlying redundant functions of the YTHDF proteins

Zou, Zhongyu; Sepich‐Poore, Caraline; Zhou, Xiaoming; Wei, Jiangbo; He, Chuan

doi:10.1186/s13059-023-02862-8

Cited by 46 publications

(38 citation statements)

References 47 publications

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“…Dependence on m6A has been shown for YTHDF proteins, which promote m6A-mediated degradation in proportion to the number of m6A sites in the transcript (Boo et al, 2022; Zaccara & Jaffrey, 2020; Zou et al, 2023). In contrast, our datasuggest an m6A-independent effect of YTHDC1 in mediating the RNAPII pausing/release process, as pause release did not show a clear correlation with the presence of m6A sites despite the binding of YTHDC1 to the regulated genes (Fig.…”

Section: Discussionmentioning

confidence: 99%

YTHDC1 m6A-dependent and m6A-independent functions converge to preserve DNA damage response.

Elvira-Blázquez,

Fernández-Justel,

Arcas

et al. 2024

Preprint

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Cells have evolved a robust and highly regulated DNA damage response to preserve their genomic integrity. Although increasing evidence highlights the relevance of RNA regulation, our understanding of its impact on a fully efficient DNA damage response remains limited. Here, through a targeted CRISPR-knockout screen, we identified RNA binding proteins and modifiers that participate in mediating the p53 response. Among the top hits, m6A reader YTHDC1 was identified as a master regulator of p53 expression. YTHDC1 binds to the transcription start sites of TP53 and other genes involved in DNA damage response, promoting their transcriptional elongation. YTHDC1 deficiency leads to reduced TP53 expression, and also retention of introns leading to aberrant protein production of key DNA damage factors. While intron retention is dependent on m6A, YTHDC1 favors TP53 transcriptional pause-release independently of m6A. Depletion of YTHDC1 causes genomic instability and aberrant cancer cell proliferation mediated by genes regulated by YTHDC1. Our results uncover YTHDC1 as an orchestrator of the DNA damage response through distinct mechanisms of co-transcriptional mRNA regulation.

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Section: Discussionmentioning

confidence: 99%

YTHDC1 m6A-dependent and m6A-independent functions converge to preserve DNA damage response.

Elvira-Blázquez,

Fernández-Justel,

Arcas

et al. 2024

Preprint

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“…However, a recent study found dynamic levels of O -GlcNAc modifications appearing on YTHDF1/3 proteins, but not YTHDF2, dependent on background, indicating that they do have diverse functions [ 41 ]. Nevertheless, it is important to interpret RNA stability data from triple YTHDF1/2/3 knockdown/knockout experiments with care, as depletion of all three YTHDF proteins results in an increase in cellular P-body formation in HeLa cells, consequently leading to the global stabilisation of most mRNAs which is not strictly dependent on m 6 A [ 42 ].…”

Section: A Promotes Rna Degradationmentioning

confidence: 99%

RNA m6A modification, signals for degradation or stabilisation?

Wei

2024

Biochemical Society Transactions

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The RNA modification N6-methyladenosine (m6A) is conserved across eukaryotes, and profoundly influences RNA metabolism, including regulating RNA stability. METTL3 and METTL14, together with several accessory components, form a ‘writer’ complex catalysing m6A modification. Conversely, FTO and ALKBH5 function as demethylases, rendering m6A dynamic. Key to understanding the functional significance of m6A is its ‘reader' proteins, exemplified by YTH-domain-containing proteins (YTHDFs) canonical reader and insulin-like growth factor 2 mRNA-binding proteins (IGF2BPs) non-canonical reader. These proteins play a crucial role in determining RNA stability: YTHDFs mainly promote mRNA degradation through different cytoplasmic pathways, whereas IGF2BPs function to maintain mRNA stability. Additionally, YTHDC1 functions within the nucleus to degrade or protect certain m6A-containing RNAs, and other non-canonical readers also contribute to RNA stability regulation. Notably, m6A regulates retrotransposon LINE1 RNA stability and/or transcription via multiple mechanisms. However, conflicting observations underscore the complexities underlying m6A's regulation of RNA stability depending upon the RNA sequence/structure context, developmental stage, and/or cellular environment. Understanding the interplay between m6A and other RNA regulatory elements is pivotal in deciphering the multifaceted roles m6A plays in RNA stability regulation and broader cellular biology.

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“…This mapping identified high-scoring interactions with mRNA silencing factors such as the CCR4-NOT deadenylase complex, the exoribonuclease XRN1, and the translational repressor DDX6 14 . By contrast, Zou et al argued that YTHDF1, 2 and 3 have distinct partners using C-terminal BirA fusions, assuming that YTHDF1 is found with translation machineries such as initiation factors (eIFs), while YTHDF2 associates better with mRNA silencing factors, and YTHDF3 is in the margin between YTHDF1 and 2 17 .…”

Section: Introductionmentioning

confidence: 99%

The YTHDF1-3 proteins are bidirectionally influenced by the codon content of their mRNA targets

Moch,

Zou,

Pythoud

et al. 2023

Preprint

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N6-methyladenosine (m6A) is the most abundant modification in eukaryotic mRNAs and plays critical roles in a broad variety of biological processes. Recognition of m6A by the YTHDF1-3 proteins results in the alteration of the translation efficiency and stability of methylated mRNAs, although their mode of action is still matter of debates. To decode the molecular basis of YTHDF1-3 action in human cells, we performed an unbiased proteomic screen of their full spectrum of interacting proteins using BioID (proximity-dependent biotin identification). Our systematic BioID mapping revealed that each YTHDF protein is a dynamic hub that associates with both mRNA silencing machineries and the translation apparatus. Based on this, we identified a direct interaction between YTHDF2 and the ribosomal protein RACK1, and found that the silencing activity of YTHDF2 is bidirectionally modulated by the codon content of its targeted mRNAs. Using a tethering reporter system that recapitulates this phenomenon, we confirmed that the three YTHDF proteins selectively repress mRNAs enriched in optimal codons, while they activate those enriched in non-optimal codons. Altogether, these results have important implications for understanding the underlying multiplicity of YTHDF1-3 and could reconcile seemingly contradictory data.

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The mechanism underlying redundant functions of the YTHDF proteins

Cited by 46 publications

References 47 publications

YTHDC1 m6A-dependent and m6A-independent functions converge to preserve DNA damage response.

YTHDC1 m6A-dependent and m6A-independent functions converge to preserve DNA damage response.

RNA m6A modification, signals for degradation or stabilisation?

The YTHDF1-3 proteins are bidirectionally influenced by the codon content of their mRNA targets

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