| 1. |
- Kayhanian, Hamzeh, et al.
(författare)
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Homopolymer switches mediate adaptive mutability in mismatch repair-deficient colorectal cancer
- 2024
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Ingår i: Nature Genetics. - 1061-4036. ; 56:7, s. 1420 -1433
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Tidskriftsartikel (refereegranskat)abstract
- Mismatch repair (MMR)-deficient cancer evolves through the stepwise erosion of coding homopolymers in target genes. Curiously, the MMR genes MutS homolog 6 (MSH6) and MutS homolog 3 (MSH3) also contain coding homopolymers, and these are frequent mutational targets in MMR-deficient cancers. The impact of incremental MMR mutations on MMR-deficient cancer evolution is unknown. Here we show that microsatellite instability modulates DNA repair by toggling hypermutable mononucleotide homopolymer runs in MSH6 and MSH3 through stochastic frameshift switching. Spontaneous mutation and reversion modulate subclonal mutation rate, mutation bias and HLA and neoantigen diversity. Patient-derived organoids corroborate these observations and show that MMR homopolymer sequences drift back into reading frame in the absence of immune selection, suggesting a fitness cost of elevated mutation rates. Combined experimental and simulation studies demonstrate that subclonal immune selection favors incremental MMR mutations. Overall, our data demonstrate that MMR-deficient colorectal cancers fuel intratumor heterogeneity by adapting subclonal mutation rate and diversity to immune selection.
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| 2. |
- Bai, Bing, et al.
(författare)
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Extensive translational regulation during seed germination revealed by polysomal profiling
- 2017
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Ingår i: New Phytologist. - : Wiley. - 0028-646X .- 1469-8137. ; 214:1, s. 233-244
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Tidskriftsartikel (refereegranskat)abstract
- This work investigates the extent of translational regulation during seed germination. The polysome occupancy of each gene is determined by genome-wide profiling of total mRNA and polysome-associated mRNA. This reveals extensive translational regulation during Arabidopsis thaliana seed germination. The polysome occupancy of thousands of individual mRNAs changes to a large extent during the germination process. Intriguingly, these changes are restricted to two temporal phases (shifts) during germination, seed hydration and germination. Sequence features, such as upstream open reading frame number, transcript length, mRNA stability, secondary structures, and the presence and location of specific motifs correlated with this translational regulation. These features differed significantly between the two shifts, indicating that independent mechanisms regulate translation during seed germination. This study reveals substantial translational dynamics during seed germination and identifies development-dependent sequence features and cis elements that correlate with the translation control, uncovering a novel and important layer of gene regulation during seed germination.
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| 3. |
- Bai, Bing, et al.
(författare)
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Seed-Stored mRNAs that Are Specifically Associated to Monosomes Are Translationally Regulated during Germination
- 2020
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Ingår i: Plant Physiology. - Rockville : American Society for Plant Biologists. - 0032-0889 .- 1532-2548. ; 182:1, s. 378-392
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Tidskriftsartikel (refereegranskat)abstract
- The life cycle of many organisms includes a quiescent stage, such as bacterial or fungal spores, insect larvae, or plant seeds. Common to these stages is their low water content and high survivability during harsh conditions. Upon rehydration, organisms need to reactivate metabolism and protein synthesis. Plant seeds contain many mRNAs that are transcribed during seed development. Translation of these mRNAs occurs during early seed germination, even before the requirement of transcription. Therefore, stored mRNAs are postulated to be important for germination. How these mRNAs are stored and protected during long-term storage is unknown. The aim of this study was to investigate how mRNAs are stored in dry seeds and whether they are indeed translated during seed germination. We investigated seed polysome profiles and the mRNAs and protein complexes that are associated with these ribosomes in seeds of the model organism Arabidopsis (Arabidopsis thaliana). We showed that most stored mRNAs are associated with monosomes in dry seeds; therefore, we focus on monosomes in this study. Seed ribosome complexes are associated with mRNA-binding proteins, stress granule, and P-body proteins, which suggests regulated packing of seed mRNAs. Interestingly, similar to 17% of the mRNAs that are specifically associated with monosomes are translationally up-regulated during seed germination. These mRNAs are transcribed during seed maturation, suggesting a role for this developmental stage in determining the translational fate of mRNAs during early germination.
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| 4. |
- Bai, Bing, et al.
(författare)
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SeedTransNet : a directional translational network revealing regulatory patterns during seed maturation and germination
- 2023
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Ingår i: Journal of Experimental Botany. - : Oxford University Press. - 0022-0957 .- 1460-2431. ; 74:7, s. 2416-2432
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Tidskriftsartikel (refereegranskat)abstract
- Seed maturation is the developmental process that prepares the embryo for the desiccated waiting period before germination. It is associated with a series of physiological changes leading to the establishment of seed dormancy, seed longevity, and desiccation tolerance. We studied translational changes during seed maturation and observed a gradual reduction in global translation during seed maturation. Transcriptome and translatome profiling revealed specific reduction in the translation of thousands of genes. By including previously published data on germination and seedling establishment, a regulatory network based on polysome occupancy data was constructed: SeedTransNet. Network analysis predicted translational regulatory pathways involving hundreds of genes with distinct functions. The network identified specific transcript sequence features suggesting separate translational regulatory circuits. The network revealed several seed maturation-associated genes as central nodes, and this was confirmed by specific seed phenotypes of the respective mutants. One of the regulators identified, an AWPM19 family protein, PM19-Like1 (PM19L1), was shown to regulate seed dormancy and longevity. This putative RNA-binding protein also affects the translational regulation of its target mRNA, as identified by SeedTransNet. Our data show the usefulness of SeedTransNet in identifying regulatory pathways during seed phase transitions.
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| 5. |
- van der Horst, Sjors, et al.
(författare)
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Metabolite Control of Translation by Conserved Peptide uORFs : The Ribosome as a Metabolite Multisensor
- 2020
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Ingår i: Plant Physiology. - Rockville : American Society for Plant Biologists. - 0032-0889 .- 1532-2548. ; 182:1, s. 110-122
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Tidskriftsartikel (refereegranskat)abstract
- The regulation of gene expression is intensely investigated in diverse biological systems. Gene expression involves RNA transcription, RNA splicing, RNA stability, translation, posttranslational modification, and protein stability. Particular attention has been given to mRNA levels due to advances in microarray analysis and RNA-sequencing techniques. However, transcript levels do not necessarily correlate with protein levels or functionality (Conrads et al., 2005; Gibon et al., 2006; Bianchini et al., 2008), and complex layers of posttranscriptional regulation have been uncovered, foremost mRNA translation. Translation can be regulated both globally and in a transcript-specific manner. Examples of global mRNA translational regulation include availability of ribosomes and translation initiation, elongation, and termination factors. In transcript-specific translational regulation, individual mRNA species or mRNA groups are selectively translated. For example, mRNAs can be sequestered in stress granules, removing them from the translatable mRNA pool (Chantarachot and BaileySerres, 2018). mRNA sequence or structural features can affect translatability directly or indirectly, the latter via small RNAs or mRNA-binding proteins (for review, see Merchante et al., 2017). Upstream open reading frames (uORFs) have been shown to participate in both global and transcript-specific regulation (von Arnim et al., 2014). Here, recent advances in translation regulation by uORFs are discussed, focusing on uORFs encoding sequence-conserved peptides (CPuORFs).
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| 6. |
- van der Horst, Sjors, et al.
(författare)
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Novel pipeline identifies new upstream ORFs and non-AUG initiating main ORFs with conserved amino acid sequences in the 5 ' leader of mRNAs in Arabidopsis thaliana
- 2019
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Ingår i: RNA. - : Cold Spring Harbor Laboratory Press (CSHL). - 1355-8382 .- 1469-9001. ; 25:3, s. 292-304
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Tidskriftsartikel (refereegranskat)abstract
- Eukaryotic mRNAs contain a 5' leader sequence preceding the main open reading frame (mORF) and, depending on the species, 20%-50% of eukaryotic mRNAs harbor an upstream ORF (uORF) in the 5' leader. An unknown fraction of these uORFs encode sequence conserved peptides (conserved peptide uORFs, CPuORFs). Experimentally validated CPuORFs demonstrated to regulate the translation of downstream mORFs often do so in a metabolite concentration-dependent manner. Previous research has shown that most CPuORFs possess a start codon context suboptimal for translation initiation, which turns out to be favorable for translational regulation. The suboptimal initiation context may even include non-AUG start codons, which makes CPuORFs hard to predict. For this reason, we developed a novel pipeline to identify CPuORFs unbiased of start codon using well-annotated sequence data from 31 eudicot plant species and rice. Our new pipeline was able to identify 29 novel Arabidopsis thaliana (Arabidopsis) CPuORFs, conserved across a wide variety of eudicot species of which 15 do not initiate with an AUG start codon. In addition to CPuORFs, the pipeline was able to find 14 conserved coding regions directly upstream and in frame with the mORF, which likely initiate translation on a non-AUG start codon. Altogether, our pipeline identified highly conserved coding regions in the 5' leaders of Arabidopsis transcripts, including in genes with proven functional importance such as LHY, a key regulator of the circadian clock, and the RAPTOR1 subunit of the target of rapamycin (TOR) kinase.
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