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October 1994 - present
October 1994 - present
Publications
Publications (146)
Ribosome synthesis begins in the nucleolus with 90S pre-ribosome construction, but little is known about how the many different snoRNAs that modify the pre-rRNA are timely guided to their target sites. Here, we report a role for Cms1 in such a process. Initially, we discovered CMS1 as a null suppressor of a nop14 mutant impaired in Rrp12-Enp1 facto...
7SK non-coding RNA (7SK) negatively regulates RNA polymerase II (RNA Pol II) elongation by inhibiting positive transcription elongation factor b (P-TEFb), and its ribonucleoprotein complex (RNP) is hijacked by HIV-1 for viral transcription and replication. Methylphosphate capping enzyme (MePCE) and La-related protein 7 (Larp7) constitutively associ...
Site-specific pseudouridylation of human ribosomal and spliceosomal RNAs is directed by H/ACA guide RNAs composed of two hairpins carrying internal pseudouridylation guide loops. The distal “antisense” sequences of the pseudouridylation loop base-pair with the target RNA to position two unpaired target nucleotides 5′-UN-3′, including the 5′ substra...
Conversion of promoter-proximally paused RNA polymerase II (RNAPII) into elongating polymerase by the positive transcription elongation factor b (P-TEFb) is a central regulatory step of mRNA synthesis. The activity of P-TEFb is controlled mainly by the 7SK small nuclear ribonucleoprotein (snRNP), which sequesters active P-TEFb into inactive 7SK/P-T...
Site-specific 2'-O-ribose methylation of mammalian rRNAs and RNA polymerase II-synthesized spliceosomal small nuclear RNAs (snRNAs) is mediated by small nucleolar and small Cajal body (CB)-specific box C/D ribonucleoprotein particles (RNPs) in the nucleolus and the nucleoplasmic CBs, respectively. Here, we demonstrate that 2'-O-methylation of the C...
Cytoplasmic localization, stability and translation of mRNAs are controlled by their dynamic association of numerous mRNA-binding (mRNP) proteins, including cold shock domain- (CSD)-containing proteins, heterogeneous nuclear ribonucleoproteins (hnRNPs) and serine/arginine-rich (SR) proteins. Here, we demonstrate that the most abundant human mRNP pr...
The 7SK small nuclear RNA is a multifunctional transcriptional regulatory RNA that controls the nuclear activity of the positive transcription elongation factor b (P-TEFb), specifically targets P-TEFb to the promoter regions of selected protein-coding genes and promotes transcription of RNA polymerase II-specific spliceosomal small nuclear RNA gene...
The 7SK small nuclear RNP (snRNP), composed of the 7SK small nuclear RNA (snRNA), MePCE, and Larp7, regulates the mRNA elon-gation capacity of RNA polymerase II (RNAPII) through controlling the nuclear activity of positive transcription elongation factor b (P-TEFb). Here, we demonstrate that the human 7SK snRNP also functions as a canonical transcr...
Mammalian cells express hundreds of intron-encoded box H/ACA RNAs which fold into a common hairpin-hinge-hairpin-tail structure, interact with four evolutionarily conserved proteins, dyskerin, Nop10, Nhp2 and Gar1, and function mainly in RNA pseudouridylation. The human telomerase H/ACA RNA (hTR) directs telomeric DNA synthesis and it carries a 5′-...
Human polypyrimidine tract-binding protein PTB is a multifunctional RNA-binding protein with four RNA recognition motifs (RRM1
to RRM4). PTB is a nucleocytoplasmic shuttle protein that functions as a key regulator of alternative pre-mRNA splicing in
the nucleoplasm and promotes internal ribosome entry site-mediated translation initiation of viral a...
Post-transcriptional pseudouridylation and 2′-O-methylation of splicesomal small nuclear ribonucleic acids (snRNAs) is mediated
by box H/ACA and box C/D small Cajal body (CB)-specific ribonucleoproteins (scaRNPs), respectively. The WD-repeat protein
79 (WDR79) has been proposed to interact with both classes of modification scaRNPs and target them i...
Through controlling the nuclear level of active positive transcription elongation factor b (P-TEFb), the 7SK small nuclear
RNA (snRNA) functions as a key regulator of RNA polymerase II transcription. Together with hexamethylene bisacetamide-inducible
proteins 1/2 (HEXIM1/2), the 7SK snRNA sequesters P-TEFb into transcriptionally inactive ribonucleo...
S6 kinases (S6Ks) are mechanistic target of rapamycin substrates that participate in cell growth control. S6Ks phosphorylate ribosomal protein S6 (rpS6) and additional proteins involved in the translational machinery, although the functional roles of these modifications remain elusive. Here we analyze the S6K-dependent transcriptional and translati...
Alu repetitive sequences are the most abundant short interspersed DNA elements in the human genome. Full-length Alu elements are composed of two tandem sequence monomers, the left and right Alu arms, both derived from the 7SL signal recognition particle RNA. Since Alu elements are common in protein-coding genes, they are frequently transcribed into...
Le nucleole a ete la premiere structure subnucleaire decrite par les microscopistes, et a longtemps ete considere comme un organite hautement specialise dans la biosynthese des ribosomes. Plus d'un siecle apres sa decouverte, des etudes recentes ont montre que le nucleole est egalement utilise par la cellule pour accomplir des fonctions cellulaires...
Apart from microRNAs, little is known about the regulation of expression of non-coding RNAs in cancer. We investigated whether small nucleolar RNAs (snoRNAs) accumulation displayed specific signatures in acute myeloblastic and acute lymphoblastic leukemias. Using microarrays and high-throughput quantitative PCR (qPCR), we demonstrate here that snoR...
Ribosome production, one of the most energy-consuming biosynthetic activities in living cells, is adjusted to growth conditions
and coordinated with the cell cycle. Connections between ribosome synthesis and cell cycle progression have been described,
but the underlying mechanisms remain only partially understood. The human HCA66 protein was recent...
P-TEFb stimulates transcription elongation by phosphorylating the carboxy-terminal domain of RNA pol II and antagonizing the effects of negative elongation factors. Its cellular availability is controlled by an abundant non coding RNA, conserved through evolution, the 7SK RNA. Together with the HEXIM proteins, 7SK RNA associates with and sequesters...
Yeast snR30 is an essential box H/ACA small nucleolar RNA (snoRNA) that promotes 18S rRNA processing through forming transient
base-pairing interactions with the newly synthesized 35S pre-rRNA. By using a novel tandem RNA affinity selection approach,
followed by coimmunoprecipitation and in vivo cross-linking experiments, we demonstrate that in add...
The carboxy-terminal domain (CTD) of the large subunit of RNA polymerase II (Pol II) comprises multiple heptapeptide repeats of the consensus Tyr1-Ser2-Pro3-Thr4-Ser5-Pro6-Ser7. Reversible phosphorylation of Ser2, Ser5, and Ser7 during the transcription cycle mediates the sequential recruitment of transcription/RNA processing factors. Phosphorylati...
Comparison of the positively charged RNA-binding motifs of HIV Tat and HEXIM proteins. HIV Tat (AAC29057), human (NM_006460; NM_144608), Xenopus laevis (NP_001090038), Salmo salar (NP_001133431), Danio rerio (NP_001091859), Ciona intestinalis (XP_002128947), Ixodes scapularis (XP_002408010), Strongylocentrotus purpuratus (XP_792438) and Nematostell...
The human immunodeficiency virus 1 (HIV-1) transcriptional transactivator (Tat) is essential for synthesis of full-length transcripts from the integrated viral genome by RNA polymerase II (Pol II). Tat recruits the host positive transcription elongation factor b (P-TEFb) to the HIV-1 promoter through binding to the transactivator RNA (TAR) at the 5...
Box H/ACA RNAs represent an abundant, evolutionarily conserved class of small noncoding RNAs. All H/ACA RNAs associate with a common set of proteins, and they function as ribonucleoprotein (RNP) enzymes mainly in the site-specific pseudouridylation of ribosomal RNAs (rRNAs) and small nuclear RNAs (snRNAs). Some H/ACA RNPs function in the nucleolyti...
The U1 small nuclear RNA (snRNA)--in the form of the U1 spliceosomal Sm small nuclear ribonucleoprotein particle (snRNP) that contains seven Sm and three U1-specific RNP proteins-has a crucial function in the recognition and removal of pre-messenger RNA introns. Here, we show that a fraction of human U1 snRNA specifically associates with the nuclea...
The H/ACA RNAs represent an abundant, evolutionarily conserved and functionally diverse class of non-coding RNAs. Many H/ACA RNAs direct pseudouridylation of rRNAs and snRNAs, while members of the rapidly growing group of 'orphan' H/ACA RNAs participate in pre-rRNA processing, telomere synthesis and probably, in other nuclear processes. The yeast s...
Supplementary Information
RNA-binding proteins of the L7Ae family are at the heart of many essential ribonucleoproteins (RNPs), including box C/D and H/ACA small nucleolar RNPs, U4 small nuclear RNP, telomerase, and messenger RNPs coding for selenoproteins. In this study, we show that Nufip and its yeast homologue Rsa1 are key components of the machinery that assembles thes...
The RNA component of human telomerase (hTR) includes H/ACA and CR7 domains required for 3' end processing, localization, and accumulation. The terminal loop of the CR7 domain contains the CAB box (ugAG) required for targeting of scaRNAs to Cajal bodies (CB) and an uncharacterized sequence required for accumulation and processing. To dissect out the...
The 7SK small nuclear RNA (snRNA) regulates RNA polymerase II transcription elongation by controlling the protein kinase activity of the positive transcription elongation factor b (P-TEFb). In cooperation with HEXIM1, the 7SK snRNA sequesters P-TEFb into the kinase-inactive 7SK/HEXIM1/P-TEFb small nuclear ribonucleoprotein (snRNP), and thereby, con...
In eukaryotic cells, a large number of box C/D and H/ACA small nucleolar RNAs (snoRNAs) direct the site-specific 2′-O-ribose methylation and pseudouridylation of rRNAs, respectively. The snoRNAs function in the form of small nucleolar RNPs (snoRNPs), each of which consists of a box C/D or box H/ACA guide RNA and four associated C/D or H/ACA snoRNP...
Les ARNs H/ACA remplissent des fonctions variées dans la cellule. Ils servent d'ARNs
guides pour les conversions d'uridines en pseudouridines des ARNs ribosomiques mais
également des snARNs du spliceosome. Les ARNs H/ACA nucléolaires, les snoARNs,
guident les modifications des ARNr alors que ce sont des ARNs H/ACA qui s'accumulent
dans les Cajal bo...
Processing from pre-mRNA introns is a widespread mechanism to generate human box C/D and H/ACA snoRNAs. Recent studies revealed
that an optimal position relative to the 3′ splice site is important for efficient processing of most box C/D snoRNAs and
that assembly of box C/D snoRNPs is stimulated by splicing factors likely bound to the branch point...
Telomerase is a ribonucleoprotein enzyme that counteracts replicative telomere erosion by adding telomeric sequence repeats onto chromosome ends. Despite its well-established role in telomere synthesis, telomerase has not yet been detected at telomeres. The RNA component of human telomerase (hTR) resides in the nucleoplasmic Cajal bodies (CBs) of i...
Box C/D and H/ACA snoRNAs represent two abundant groups of small noncoding RNAs. The majority of box C/D and H/ACA snoRNAs function as guide RNAs in the site-specific 2'-O-methylation and pseudouridylation of rRNAs, respectively. The box C/D snoRNAs associate with fibrillarin, Nop56, Nop58, and 15.5K/NHPX proteins to form functional snoRNP particle...
The positive transcription elongation factor b (P-TEFb), a complex of Cdk9 and cyclin T1/T2, stimulates transcription by phosphorylating RNA polymerase II. The 7SK small nuclear RNA, in cooperation with HEXIM1 protein, functions as a general polymerase II transcription regulator by sequestering P-TEFb into a large kinase-inactive 7SK/HEXIM1/P-TEFb...
To better understand intranuclear-targeting mechanisms, we have studied the transport of U3 snoRNA in human cells. Surprisingly, we found that PHAX, the snRNA export adaptor, is highly enriched in complexes containing m7G-capped U3 precursors. In contrast, the export receptor CRM1 is predominantly bound to TMG-capped U3 species. In agreement, PHAX...
The nucleus contains a large number of metabolically stable, 60-450-nt-long small nuclear RNAs (snRNAs) that exist in the form of ribonucleoproteins (snRNPs) ([Yu et al., 1999][1]). Each snRNP is composed of an snRNA and a set of associated RNP proteins. Based on their function and intranuclear
Pseudouridine, the most abundant modified nucleoside in RNA, is synthesized by posttranscriptional isomerization of uridines.
In eukaryotic RNAs, site-specific synthesis of pseudouridines is directed primarily by box H/ACA guide RNAs. In this study,
we have identified 61 novel putative pseudouridylation guide RNAs by construction and characterizati...
Telomerase is a ribonucleoprotein reverse transcriptase that uses its RNA component as a template for synthesis of telomeric DNA repeats at the ends of linear eukaryotic chromosomes. Here, fluorescence in situ hybridization demonstrates that in HeLa cancer cells, human telomerase RNA (hTR) accumulates in the nucleoplasmic Cajal bodies (CBs). Locali...
Saccharomyces cerevisiae snR30 is an essential box H/ACA small nucleolar RNA (snoRNA) required for the processing of 18S rRNA.
Here, we show that the previously characterized human, reptilian, amphibian, and fish U17 snoRNAs represent the vertebrate
homologues of yeast snR30. We also demonstrate that U17/snR30 is present in the fission yeast Schizo...
Pseudouridines and 2'-O-methylated nucleotides are ubiquitous constituents of stable cellular RNAs. In eukaryotes, posttranscriptional synthesis of most pseudouridines and 2'-O-methylated nucleotides is directed by sequence-specific guide RNAs (gRNAs). In recent years, an enormous number of novel putative modification gRNAs have been identified in...
Post-transcriptional synthesis of 2'-O-methylated nucleotides and pseudouridines in Sm spliceosomal small nuclear RNAs takes place in the nucleoplasmic Cajal bodies and it is directed by guide RNAs (scaRNAs) that are structurally and functionally indistinguishable from small nucleolar RNAs (snoRNAs) directing rRNA modification in the nucleolus. The...
Biogenesis of functional spliceosomal small nuclear RNAs (snRNAs) includes the post-transcriptional covalent modification of numerous internal nucleotides. We have recently demonstrated that synthesis of 2'-O-methylated nucleotides and pseudouridines in the RNA polymerase II-synthesized Sm snRNAs is directed by sequence-specific guide RNAs. Here, w...
Site‐specific post‐transcriptional conversion of uridines to pseudouridine in ribosomal RNAs and small nuclear RNAs (snRNAs)
is directed by guide RNAs which possess the conserved box H and ACA sequence elements and fold into the consensus ‘hairpin–hinge–hairpin–tail’
secondary structure. Here, we describe an unusual mammalian pseudouridylation guid...
Cajal (coiled) bodies are conserved subnuclear organelles that are present in the nucleoplasm of both animal and plant cells. Although Cajal bodies were first described nearly 100 years ago, their function has remained largely speculative. Here, we describe a novel class of human small nuclear RNAs that localize specifically to Cajal bodies. The sm...
Small nucleolar RNAs represent an abundant, evolutionarily ancient group of noncoding RNAs which possess impressively diverse functions ranging from 2'-O-methylation and pseudouridylation of various classes of RNAs, through nucleolytic processing of rRNAs to the synthesis of telomeric DNA.
Telomerase is a ribonucleoprotein reverse transcriptase that synthesises telomeric DNA. The RNA component of telomerase acts as a template for telomere synthesis and binds the reverse transcriptase. In this study, we have performed in vivo and in vitro structural analyses of human telomerase RNA (hTR). In vivo mapping experiments showed that the 5'...
The transcription of eukaryotic protein-coding genes involves complex regulation of RNA polymerase (Pol) II activity in response to physiological conditions and developmental cues. One element of this regulation involves phosphorylation of the carboxy-terminal domain (CTD) of the largest polymerase subunit by a transcription elongation factor, P-TE...
The nucleolus was the first subnuclear structure described by early microscopists, and has long been considered as a highly specialised organelle, fully dedicated to the biogenesis of cytoplasmic ribosomes. However, over the past few years, a spate of studies has implicated the nucleolus in various cellular processes, including biogenesis of small...
In eukaryotes, two distinct classes of small nucleolar RNAs (snoRNAs), namely the fibrillarin-associated box C/D snoRNAs and the Gar1p-associated box H/ACA snoRNAs, direct the site-specific 2'-O-ribose methylation and pseudouridylation of ribosomal RNAs (rRNAs), respectively. We have identified a novel evolutionarily conserved snoRNA, called U85, w...
The C and D box-containing (box C/D) small nucleolar RNAs (snoRNAs) function in the nucleolytic processing and 2′-O-methylation of precursor rRNA. In vertebrates, most box C/D snoRNAs are processed from debranched pre-mRNA introns by exonucleolytic
activities. Elements directing accurate snoRNA excision are located within the snoRNA itself; they co...