Their ability to move within genomes gives transposable elements an intrinsic propensity to affect genome evolution. Non-long terminal repeat (LTR) retrotransposons — including LINE-1, Alu and SVA elements — have proliferated over the past 80 million years of primate evolution and now account for approximately one-third of the human genome. In this Review, we focus on this major class of elements and discuss the many ways that they affect the human genome: from generating insertion mutations and genomic instability to altering gene expression and contributing to genetic innovation. Increasingly detailed analyses of human and other primate genomes are revealing the scale and complexity of the past and current contributions of non-LTR retrotransposons to genomic change in the human lineage.

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The impact of retrotransposons on human genome evolution.

Nonsense-mediated mRNA decay (NMD) is probably the best characterized eukaryotic RNA degradation pathway. Through intricate steps, a set of NMD factors recognize and degrade mRNAs with translation termination codons that are positioned in abnormal contexts. However, NMD is not only part of a general cellular quality control system that prevents the production of aberrant proteins. Mammalian cells also depend on NMD to dynamically adjust their transcriptomes and their proteomes to varying physiological conditions. In this Review, we discuss how NMD targets mRNAs, the types of mRNAs that are targeted, and the roles of NMD in cellular stress, differentiation and maturation processes.

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Nonsense-mediated mRNA decay: an intricate machinery that shapes transcriptomes.

In the year 2003 there was a 17% increase in the number of publications citing work performed using optical biosensor technology compared with the previous year. We collated the 962 total papers for 2003, identified the geographical regions where the work was performed, highlighted the instrument types on which it was carried out, and segregated the papers by biological system. In this overview, we spotlight 13 papers that should be on everyone's 'must read' list for 2003 and provide examples of how to identify and interpret high-quality biosensor data. Although we still find that the literature is replete with poorly performed experiments, over-interpreted results and a general lack of understanding of data analysis, we are optimistic that these shortcomings will be addressed as biosensor technology continues to mature.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/jmr.753

Survey of the year 2003 commercial optical biosensor literature

Nonsense-mediated mRNA decay (NMD) is one of the best characterized and most evolutionarily conserved cellular quality control mechanisms. Although NMD was first found to target one-third of mutated, disease-causing mRNAs, it is now known to also target ~10% of unmutated mammalian mRNAs to facilitate appropriate cellular responses — adaptation, differentiation or death — to environmental changes. Mutations in NMD genes in humans are associated with intellectual disability and cancer. In this Review, we discuss how NMD serves multiple purposes in human cells by degrading both mutated mRNAs to protect the integrity of the transcriptome and normal mRNAs to control the quantities of unmutated transcripts. Nonsense-mediated mRNA decay (NMD) is a quality and quantity control mechanism for degrading mutated mRNAs to protect the integrity of the transcriptome and proteome and unmutated mRNAs to control their quantity. NMD dysfunction in humans is associated with intellectual disability and cancer.

/pdf/quality-and-quantity-control-of-gene-expression-by-nonsense-19zmyczt2k.pdf

Quality and quantity control of gene expression by nonsense-mediated mRNA decay

SARS-CoV-2 Disrupts Splicing, Translation, and Protein Trafficking to Suppress Host Defenses.

Nonsense-mediated mRNA decay (NMD) is an mRNA quality-control mechanism that typifies all eukaryotes examined to date. NMD surveys newly synthesized mRNAs and degrades those that harbor a premature termination codon (PTC), thereby preventing the production of truncated proteins that could result in disease in humans. This is evident from dominantly inherited diseases that are due to PTC-containing mRNAs that escape NMD. Although many cellular NMD targets derive from mistakes made during, for example, pre-mRNA splicing and, possibly, transcription initiation, NMD also targets ∼10% of normal physiological mRNAs so as to promote an appropriate cellular response to changing environmental milieus, including those that induce apoptosis, maturation or differentiation. Over the past ∼35 years, a central goal in the NMD field has been to understand how cells discriminate mRNAs that are targeted by NMD from those that are not. In this Cell Science at a Glance and the accompanying poster, we review progress made towards this goal, focusing on human studies and the role of the key NMD factor up-frameshift protein 1 (UPF1).

/pdf/nonsense-mediated-mrna-decay-in-humans-at-a-glance-3i0uj4a04z.pdf

Nonsense-mediated mRNA decay in humans at a glance

Nonsense-mediated mRNA decay (NMD) controls the quality of eukaryotic gene expression and also degrades physiologic mRNAs. How NMD targets are identified is incompletely understood. A central NMD factor is the ATP-dependent RNA helicase upframeshift 1 (UPF1). Neither the distance in space between the termination codon and the poly(A) tail nor the binding of steady-state, largely hypophosphorylated UPF1 is a discriminating marker of cellular NMD targets, unlike for premature termination codon (PTC)-containing reporter mRNAs when compared with their PTC-free counterparts. Here, we map phosphorylated UPF1 (p-UPF1)-binding sites using transcriptome-wide footprinting or DNA oligonucleotide-directed mRNA cleavage to report that p-UPF1 provides the first reliable cellular NMD target marker. p-UPF1 is enriched on NMD target 3′ untranslated regions (UTRs) along with suppressor with morphogenic effect on genitalia 5 (SMG5) and SMG7 but not SMG1 or SMG6. Immunoprecipitations of UPF1 variants deficient in various aspects of the NMD process in parallel with Forster resonance energy transfer (FRET) experiments reveal that ATPase/helicase-deficient UPF1 manifests high levels of RNA binding and disregulated hyperphosphorylation, whereas wild-type UPF1 releases from nonspecific RNA interactions in an ATP hydrolysis-dependent mechanism until an NMD target is identified. 3′ UTR-associated UPF1 undergoes regulated phosphorylation on NMD targets, providing a binding platform for mRNA degradative activities. p-UPF1 binding to NMD target 3′ UTRs is stabilized by SMG5 and SMG7. Our results help to explain why steady-state UPF1 binding is not a marker for cellular NMD substrates and how this binding is transformed to induce mRNA decay.

/pdf/a-post-translational-regulatory-switch-on-upf1-controls-4iwcv9ieiy.pdf

A post-translational regulatory switch on UPF1 controls targeted mRNA degradation.

Nonsense-mediated mRNA decay (NMD), which degrades transcripts harboring a premature termination codon (PTC), depends on the helicase up-frameshift 1 (UPF1). However, mRNAs that are not NMD targets also bind UPF1. What governs the timing, position, and function of UPF1 binding to mRNAs remains unclear. We provide evidence that (i) multiple UPF1 molecules accumulate on the 3′-untranslated region (3′ UTR) of PTC-containing mRNAs and to an extent that is greater per unit 3′ UTR length if the mRNA is an NMD target; (ii) UPF1 binding begins ≥35 nt downstream of the PTC; (iii) enhanced UPF1 binding to the 3′ UTR of PTC-containing mRNA relative to its PTC-free counterpart depends on translation; and (iv) the presence of a 3′ UTR exon–junction complex (EJC) further enhances UPF1 binding and/or affinity. Our data suggest that NMD involves UPF1 binding along a 3′ UTR whether the 3′ UTR contains an EJC. This binding explains how mRNAs without a 3′ UTR EJC but with an abnormally long 3′ UTR can be NMD targets, albeit not as efficiently as their counterparts that contain a 3′ UTR EJC.

https://www.pnas.org/content/pnas/110/9/3357.full.pdf

Rules that govern UPF1 binding to mRNA 3′ UTRs

Nonsense-mediated messenger RNA decay (NMD) controls mRNA quality and degrades physiologic mRNAs to fine-tune gene expression in changing developmental or environmental milieus. NMD requires that its targets are removed from the translating pool of mRNAs. Since the decay steps of mammalian NMD remain unknown, we developed assays to isolate and sequence direct NMD decay intermediates transcriptome-wide based on their co-immunoprecipitation with phosphorylated UPF1, which is the active form of this essential NMD factor. We show that, unlike steady-state UPF1, phosphorylated UPF1 binds predominantly deadenylated mRNA decay intermediates and activates NMD cooperatively from 5'- and 3'-ends. We leverage method modifications to characterize the 3'-ends of NMD decay intermediates, show that they are ribosome-bound, and reveal that some are subject to the addition of non-templated nucleotide. Uridines are added by TUT4 and TUT7 terminal uridylyl transferases and removed by the Perlman syndrome-associated exonuclease DIS3L2. The addition of other non-templated nucleotides appears to inhibit decay.

Tatsuaki Kurosaki

Papers

Quality and quantity control of gene expression by nonsense-mediated mRNA decay

Nonsense-mediated mRNA decay in humans at a glance

A post-translational regulatory switch on UPF1 controls targeted mRNA degradation.

Rules that govern UPF1 binding to mRNA 3′ UTRs

NMD-degradome sequencing reveals ribosome-bound intermediates with 3'-end non-templated nucleotides.