Protein encoded in human telomerase RNA is involved in cell protective pathways

Rubtsova, Maria P.; Naraykina, Yulia; Vasilkova, Daria; Meerson, Mark; Zvereva, Maria I.; Prassolov, Vladimir; Лазарев, В. Н.; Manuvera, Valentin A.; Kovalchuk, Sergey I.; Anikanov, Nikolay; Butenko, Ivan; Pobeguts, Olga; Govorun, Vadim M.; Донцова, О. А.

doi:10.1093/nar/gky705

Cited by 41 publications

(45 citation statements)

References 57 publications

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“…Noncoding RNAs have been shown to play central roles in biology. Key cellular machines such as telomerase and the ribosome are comprised of proteins and noncoding RNAs and serve as classic examples of RNA-based functionalities [1,2]. While thousands of lncRNA loci have been identified in mammalian genomes, characterizing their functions has been a challenge because of their diverse biological roles and due to complications in identifying their modes of action [3,4].…”

Section: Introductionmentioning

confidence: 99%

The Tug1 lncRNA locus is essential for male fertility

et al. 2020

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Background: Several long noncoding RNAs (lncRNAs) have been shown to function as components of molecular machines that play fundamental roles in biology. While the number of annotated lncRNAs in mammalian genomes has greatly expanded, studying lncRNA function has been a challenge due to their diverse biological roles and because lncRNA loci can contain multiple molecular modes that may exert function. Results: We previously generated and characterized a cohort of 20 lncRNA loci knockout mice. Here, we extend this initial study and provide a more detailed analysis of the highly conserved lncRNA locus, taurine-upregulated gene 1 (Tug1). We report that Tug1-knockout male mice are sterile with underlying defects including a low number of sperm and abnormal sperm morphology. Because lncRNA loci can contain multiple modes of action, we wanted to determine which, if any, potential elements contained in the Tug1 genomic region have any activity. Using engineered mouse models and cell-based assays, we provide evidence that the Tug1 locus harbors two distinct noncoding regulatory activities, as a cis-DNA repressor that regulates neighboring genes and as a lncRNA that can regulate genes by a trans-based function. We also show that Tug1 contains an evolutionary conserved open reading frame that when overexpressed produces a stable protein which impacts mitochondrial membrane potential, suggesting a potential third coding function. Conclusions: Our results reveal an essential role for the Tug1 locus in male fertility and uncover evidence for distinct molecular modes in the Tug1 locus, thus highlighting the complexity present at lncRNA loci.

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Section: Introductionmentioning

confidence: 99%

The Tug1 lncRNA locus is essential for male fertility

et al. 2020

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“…Recent studies have pointed to the important roles of sORFencoded peptides (SEPs) in cells (Magny et al 2013;Nelson et al 2016;D'Lima et al 2017;Huang et al 2017;Matsumoto et al 2017;Rubtsova et al 2018). However, unraveling the roles of SEPs is a challenging task, as is their detection at the biochemical level.…”

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confidence: 99%

Distinct types of short open reading frames are translated in plant cells

et al. 2019

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Genomes contain millions of short (<100 codons) open reading frames (sORFs), which are usually dismissed during gene annotation. Nevertheless, peptides encoded by such sORFs can play important biological roles, and their impact on cellular processes has long been underestimated. Here, we analyzed approximately 70,000 transcribed sORFs in the model plant Physcomitrella patens (moss). Several distinct classes of sORFs that differ in terms of their position on transcripts and the level of evolutionary conservation are present in the moss genome. Over 5000 sORFs were conserved in at least one of 10 plant species examined. Mass spectrometry analysis of proteomic and peptidomic data sets suggested that tens of sORFs located on distinct parts of mRNAs and long noncoding RNAs (lncRNAs) are translated, including conserved sORFs. Translational analysis of the sORFs and main ORFs at a single locus suggested the existence of genes that code for multiple proteins and peptides with tissue-specific expression. Functional analysis of four lncRNA-encoded peptides showed that sORFs-encoded peptides are involved in regulation of growth and differentiation in moss. Knocking out lncRNA-encoded peptides resulted in a decrease of moss growth. In contrast, the overexpression of these peptides resulted in a diverse range of phenotypic effects. Our results thus open new avenues for discovering novel, biologically active peptides in the plant kingdom.

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“…The specific identities and functional role(s) of such putative hTR folding intermediates remain to be determined; however, it is conceivable that junction nucleotides may be conserved to preserve RNA structural plasticity required for RNP assembly, as well as to mediate sequence-specific protein interactions that may or may not be present in the fully assembled RNP complex. Lastly, recent reports have suggested additional non-canonical roles of hTR that may also explain the patterns of RNA sequence conservation in CR4/5 junction region (Rubtsova et al 2018;Laudadio et al 2019).…”

Section: Discussionmentioning

confidence: 93%

Folding heterogeneity in the essential human telomerase RNA three-way junction

Palka

Forino

Henstchel

et al. 2019

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Telomeres safeguard the genome by suppressing illicit DNA damage responses at chromosome termini. In order to compensate for incomplete DNA replication at telomeres, most continually dividing cells, including many cancers, express the telomerase ribonucleoprotein (RNP) complex. Telomerase maintains telomere length by catalyzing de novo synthesis of short DNA repeats using an internal telomerase RNA (TR) template. TRs from diverse species harbor structurally conserved domains that contribute to RNP biogenesis and function. In vertebrate TRs, the conserved regions 4 and 5 (CR4/5) fold into a three-way junction (3WJ) that binds directly to the telomerase catalytic protein subunit and is required for telomerase function. We have analyzed the structural properties of the human TR (hTR) CR4/5 domain using a combination of in vitro chemical mapping, endogenous RNP assembly assays, and singlemolecule structural analysis. Our data suggest that a functionally essential stem loop within CR4/5 is not stably folded in the absence of the telomerase reverse transcriptase protein subunit in vitro. Rather, the hTR CR4/5 domain adopts a heterogeneous ensemble of conformations. RNA structural engineering intended to bias the folding landscape of the hTR CR4/5 demonstrates that a stably folded 3WJ motif is necessary but not sufficient to promote assembly of a functional RNP complex. Finally, single-molecule measurements on the hTR CR4/5 domain show that RNP assembly selects for a conformation that is not the major population in the heterogeneous free RNA ensemble, suggesting that non-canonical hTR folds may be required during telomerase biogenesis.

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Protein encoded in human telomerase RNA is involved in cell protective pathways

Cited by 41 publications

References 57 publications

The Tug1 lncRNA locus is essential for male fertility

The Tug1 lncRNA locus is essential for male fertility

Distinct types of short open reading frames are translated in plant cells

Folding heterogeneity in the essential human telomerase RNA three-way junction

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