The RNA Revolution in the Central Molecular Biology Dogma Evolution DOI Open Access
William A. Haseltine, Roberto Patarca

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(23), P. 12695 - 12695

Published: Nov. 26, 2024

Human genome projects in the 1990s identified about 20,000 protein-coding sequences. We are now RNA revolution, propelled by realization that genes determine phenotype beyond foundational central molecular biology dogma, stating inherited linear pieces of DNA transcribed to RNAs and translated into proteins. Crucially, over 95% genome, initially considered junk between genes, encodes essential, functionally diverse non-protein-coding RNAs, raising gene count at least one order magnitude. Most phenotype-determining changes regulatory areas control can directly or indirectly phenotypes regulating protein function, transferring information within organisms, generating DNA. also exhibit high structural, functional, biomolecular interaction plasticity modified via editing, methylation, glycosylation, other mechanisms, which bestow them with intra- extracellular functions without altering underlying is, therefore, currently primary determinant cellular populational functional diversity, disease-linked structural variations, cell function regulation. As demonstrated RNA-based coronavirus vaccines' success, technology is transforming medicine, agriculture, industry, as did advent recombinant 1980s.

Language: Английский

eIF4E orchestrates mRNA processing, RNA export and translation to modify specific protein production DOI Creative Commons
Jean-Clément Mars, Biljana Culjkovic‐Kraljacic, Katherine L. B. Borden

et al.

Nucleus, Journal Year: 2024, Volume and Issue: 15(1)

Published: June 16, 2024

The eukaryotic translation initiation factor eIF4E acts as a multifunctional that simultaneously influences mRNA processing, export, and in many organisms. Its multifactorial effects are derived from its capacity to bind the methyl-7-guanosine cap on 5'end of mRNAs thus can act chaperone for transcripts nucleus cytoplasm. In this review, we describe roles major mRNA-processing events including capping, splicing, cleavage polyadenylation, nuclear export translation. We discuss evidence at two levels generate widescale changes ultimately protein produced. First, alters production components processing machinery, supporting reprogramming multiple events. way, modulate without physically interacting with target transcripts. Second, also interacts both capped RNA or machineries. Further, specific sensitive only particular This selectivity is governed by presence cis-acting elements within known USER codes recruit relevant co-factors engaging appropriate machinery. all, molecular bases eIF4E's function regulatory pathways, basis selectivity, present compendium ~80 eIF4E-interacting factors which play these activities provide an overview relevance functions oncogenic potential. Finally, summarize early-stage clinical studies targeting cancer.

Language: Английский

Citations

8
The GC-content at the 5′ ends of human protein-coding genes is undergoing mutational decay DOI Creative Commons
Yi Qiu,

Yoon Mo Kang,

Christopher Korfmann

et al.

Genome biology, Journal Year: 2024, Volume and Issue: 25(1)

Published: Aug. 13, 2024

Abstract Background In vertebrates, most protein-coding genes have a peak of GC-content near their 5′ transcriptional start site (TSS). This feature promotes both the efficient nuclear export and translation mRNAs. Despite importance for RNA metabolism, its general features, origin, maintenance remain mysterious. We investigate evolutionary forces shaping at (TSS) through comparative genomic analysis nucleotide substitution rates between different species by examining human de novo mutations. Results Our data suggests that GC-peaks TSSs were present in last common ancestor amniotes, likely vertebrates. observe apes rodents, where recombination is directed away from PRDM9, end gene currently undergoing mutational decay. canids, which lack PRDM9 perform TSSs, increasing. show these patterns extend into open reading frame, thus impacting synonymous codon position choices. Conclusions results indicate dynamics this GC-peak amniotes largely shaped historic recombination. Since decay towards mutation rate equilibrium default state non-functional DNA, observed decrease rodents indicates not being maintained selection on those species.

Language: Английский

Citations

5
Critical Cellular Functions and Mechanisms of Action of the RNA Helicase UAP56 DOI

Ryan Yellamaty,

Shalini Sharma

Journal of Molecular Biology, Journal Year: 2024, Volume and Issue: 436(12), P. 168604 - 168604

Published: May 8, 2024

Language: Английский

Citations

4
Structures and mRNP remodeling mechanism of the TREX-2 complex DOI
Yihu Xie, Bradley P. Clarke, Dongqi Xie

et al.

Structure, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 1, 2025

Language: Английский

Citations

0
Advances in nuclear proteostasis of metazoans DOI Creative Commons

Julia Buggiani,

Thierry Meinnel, Carmela Giglione

et al.

Biochimie, Journal Year: 2024, Volume and Issue: 226, P. 148 - 164

Published: April 19, 2024

The proteostasis network and associated protein quality control (PQC) mechanisms ensure proteome functionality are essential for cell survival. A distinctive feature of eukaryotic cells is their high degree compartmentalization, requiring specific adapted networks each compartment. nucleus, maintaining the integrity genetic information gene transcription, one such While PQC have been investigated decades in cytoplasm endoplasmic reticulum, our knowledge nuclear pathways only emerging. Recent developments field underscored importance spatially managing aberrant proteins within nucleus. Upon proteotoxic stress, misfolded effectors accumulate various membrane-less organelles. Beyond bringing together substrates, biophysical properties these organelles allow novel functions. In this review, we explore specificity compartment, network, roles metazoans.

Language: Английский

Citations

3
Nuclear sorting of short RNA polymerase II transcripts DOI
William A. Garland, Torben Heick Jensen

Molecular Cell, Journal Year: 2024, Volume and Issue: 84(19), P. 3644 - 3655

Published: Oct. 1, 2024

Language: Английский

Citations

2
The GC-content at the 5’ends of human protein-coding genes is undergoing mutational decay DOI Creative Commons
Yi Qiu,

Yoon Mo Kang,

Christopher Korfmann

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: March 14, 2024

Abstract In vertebrates, most protein-coding genes have a peak of GC-content near their 5’ transcriptional start site (TSS). This feature promotes both the efficient nuclear export and translation mRNAs. Despite importance for RNA metabolism, its general features, origin, maintenance remain mysterious. We investigated evolutionary forces shaping at (TSS) through comparative genomic analysis nucleotide substitution rates between different species by examining human de novo mutations. Our data suggests that GC-peaks TSSs were present in last vertebrate common ancestor are largely dictated recombination patterns. observe primates rodents, where is directed away from PRDM9, gene currently undergoing mutational decay. canids, which lack PRDM9 perform TSSs, increasing. These patterns extend into open reading frame affecting regions, we show changes due to affect synonymous codon position choices frame. results indicate although high may be shaped selective pressures enhance expression, dynamics mammals recombination.

Language: Английский

Citations

1
N-6-methyladenosine (m6A) promotes the nuclear retention of mRNAs with intact 5′ splice site motifs DOI Creative Commons

Eliza S. Lee,

Harrison W. Smith, Yifan E. Wang

et al.

Life Science Alliance, Journal Year: 2024, Volume and Issue: 8(2), P. e202403142 - e202403142

Published: Dec. 3, 2024

In humans, misprocessed mRNAs containing intact 5′ Splice Site (5′SS) motifs are nuclear retained and targeted for decay by ZFC3H1, a component of the Poly(A) Exosome Targeting complex, U1-70K, U1 snRNP. S. pombe , ZFC3H1 homolog, Red1, binds to YTH domain–containing protein Mmi1 targets certain RNA transcripts foci retention decay. Here we show that YTHDC1 YTHDC2, two domain-containing proteins bind N -6-methyladenosine (m6A) modified RNAs, interact with required 5′SS motifs. Disruption m6A deposition inhibits both these their accumulation in YTHDC1-enriched adjacent speckles. Endogenous RNAs motifs, such as intronic poly-adenylated transcripts, tend be m6A-modified at low levels. Thus, modification acts on conserved quality control mechanism

Language: Английский

Citations

1
NXT2 is the key player for nuclear RNA export in the human testis and critical for spermatogenesis DOI Open Access
Ann‐Kristin Dicke, Ammar Ahmedani, Lin Ma

et al.

medRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Aug. 2, 2024

In eukaryotes, the nucleocytoplasmic export of bulk poly(A)+-mRNAs through nuclear pore complex is mediated by ubiquitously expressed NXT1-NXF1 heterodimer. humans, NXT1 has an X-chromosomal paralog, NXT2, which exhibits testis-enriched expression, suggesting a role in spermatogenesis. Here, we report vivo interaction NXT2 with crucial components machinery, including NXF1, testis-specific NXF1 paralogs NXF2 and NXF3, proteins NUP93 NUP214. Further, NXT2's NTF2-like domain mediates binding to NXF3. By identifying infertile men loss-of-function variants link impaired NXT2-NXF activity disturbed germ cell development. The predominant absence cells deficiency indicates its critical function already during fetal or first steps contrast, loss NXF3 affects later stages spermatogenesis resulting quantitatively qualitatively sperm production.

Language: Английский

Citations

0
Evolution of retrocopies in the context of HUSH silencing DOI Creative Commons
Joanna Kozłowska-Masłoń, Joanna Ciomborowska-Basheer, Magdalena Regina Kubiak

et al.

Biology Direct, Journal Year: 2024, Volume and Issue: 19(1)

Published: Aug. 2, 2024

Retrotransposition is one of the main factors responsible for gene duplication and thus genome evolution. However, sequences that undergo this process are not only an excellent source biological diversity, but in certain cases also pose a threat to integrity DNA. One mechanisms protects against incorporation mobile elements HUSH complex, which silencing long, intronless, transcriptionally active transposed rich adenine on sense strand. In study, broad sets human porcine retrocopies were analysed with respect above factors, taking into account evolution these molecules. Analysis expression pattern, genomic structure, transcript length, nucleotide substitution frequency showed strong relationship between level exon length as well protective nature introns. The results studies there no direct correlation content. protein-coding retrocopies, have lower content, significantly higher than adenine-rich non-coding expressed retrocopies. Therefore, although mechanism may be important part regulation retrocopy expression, it component more complex molecular network remains elucidated.

Language: Английский

Citations

0