Disease relevance of LSM2

• The spinal muscular atrophy disease gene product (SMN) is crucial for small nuclear ribonuclear protein (snRNP) biogenesis in the cytoplasm and plays a role in pre-mRNA splicing in the nucleus [1].
• Antibodies derived from patients with systemic lupus erythematosus (SLE) and mixed connective tissue disease (MCTD) recognize distinguishable subsets of pulse-labeled snRNP peptides [2].
• Here, we have used gene silencing to assess the effect of SMN protein deficiency on U snRNP metabolism in living cells and organisms [3].
• Autoantibodies from patients with systemic rheumatic diseases were used to map antigenic sites on the 68-kD autoantigen (p68) associated with (U1)RNA-containing small nuclear ribonucleoprotein (snRNP) particles [4].
• Autoantibodies specific against fibrillarin, a 34-kD nucleolar protein associated with U3-snRNP, are present in patients with systemic sclerosis (SSc) [5].

High impact information on LSM2

• The upstream cleavage product corresponds to the mature histone mRNA, while the downstream product is degraded by a 5'-3' exonuclease, also dependent on the U7 snRNP [6].
• On the basis of this analysis, we describe a new type of U1 snRNP binding site in an intron that is essential for accurate intron removal [7].
• The SMN-SIP1 complex has an essential role in spliceosomal snRNP biogenesis [8].
• Defects in spliceosomal snRNP biogenesis may, therefore, be the cause of SMA [8].
• The spinal muscular atrophy disease gene product, SMN, and its associated protein SIP1 are in a complex with spliceosomal snRNP proteins [9].

Chemical compound and disease context of LSM2

• SLE and mixed connective tissue disease (MCTD) are characterized by the presence of high titers of autoantibodies against uridine-rich RNA-small nuclear ribonucleoprotein (snRNP) Ag [10].
• Autoimmune disease antigen U1 snRNP neutralizes heparin [11].

Biological context of LSM2

• Together with previous results, these data indicate that methylation of Sm proteins by the methylosome directs Sm proteins to the SMN complex for assembly into snRNP core particles and suggest that the methylosome can regulate snRNP assembly [12].
• LSM 2 demonstrated the best combination of low bias [0.1% (-8.9%, 11%) and 11% (4.3%, 15%)] and high accuracy [-1.0% (-12%, 24%) and 14% (7.9%, 37%)] for temozolomide clearance and MTIC AUC, respectively [13].
• The human U1 snRNP-specific U1A protein inhibits polyadenylation of its own pre-mRNA [14].
• Oligonucleotide directed RNAase H degradation indicates that this 5' end region is available for base pairing interactions within the HSUR 1 and HSUR 2 snRNP particles [15].
• A short RNA oligonucleotide comprising the 5' splice site consensus sequence (5'SS RNA) is sufficient to bind U1 small nuclear ribonucleoprotein particle (snRNP) or to induce the association of U2 snRNP and U4-U5-U6 triple snRNP [16].

Anatomical context of LSM2

• Entry of U2 snRNP into the spliceosome is initiated by interaction of the essential splicing factor U2AF65 with the pre-mRNA polypyrimidine tract [17].
• The survival motor neuron (SMN) protein, the spinal muscular atrophy disease gene product, is crucial for snRNP core particle assembly in vivo [12].
• Analysis of the mature rRNAs and rRNA intermediates that accumulate in the U8-depleted oocytes indicate that the U8 snRNP is essential for correct maturation of the 5.8S and 28S rRNAs at both their 5' and 3' ends [18].
• cDNA encoding a 70 kd protein (70K) associated with U1 small nuclear ribonucleoprotein (snRNP) was cloned from a human brain-stem library using autoantibodies from patients with connective tissue disease [19].
• In eukaryotic cells, the conversion of gene transcripts into messenger RNA's involves multiple factors, including the highly abundant small nuclear ribonucleoprotein (snRNP) complexes that mediate the splicing reaction [20].

Associations of LSM2 with chemical compounds

• The methylosome functions to modify specific arginines to dimethylarginines in the arginine- and glycine-rich domains of several spliceosomal Sm proteins, and this modification targets these proteins to the survival of motor neurons (SMN) complex for assembly into small nuclear ribonucleoprotein (snRNP) core particles [21].
• Results from Monte-Carlo simulations also revealed that LSM 2 had the best combination of lowest bias (0.1+/-6.1% and -0.8+/-6.5%), and the highest accuracy (4.5+/-4.1% and 5.0+/-4.3%) for temozolomide clearance and MTIC apparent clearance, respectively [13].
• These antibodies were used to immunoprecipitate sucrose gradient fractionated pulse-labeled and pulse/chased snRNP proteins [2].
• A factor, U2AF, is required for U2 snRNP binding and splicing complex assembly [22].
• We have used antisense 2'-OMe RNA oligonucleotides carrying four 5'-terminal biotin residues to probe the structure and function of the human U4/U6 snRNP [23].

Physical interactions of LSM2

• SMN oligomers interact avidly with the snRNP core proteins SmB, -D1, and -D3 [1].
• Mutations in the polypyrimidine tract that reduce the binding of pPTB also reduce the efficiency of formation of the pre-spliceosome complex containing U2 snRNP [24].
• This implies that the PRMT5 complex is involved in an early stage of U7 snRNP assembly and hence may have a second snRNP assembly function unrelated to sDMA modification [25].
• We previously identified a 100-kDa zinc finger protein (ZFP100) as a component of U7 snRNP that interacts with the SLBP/pre-mRNA complex [26].
• The data indicate that SPF30 is an essential human splicing factor that may act to dock the U4/U5/U6 tri-snRNP to the A complex during spliceosome assembly or, alternatively, may act as a late assembly factor in both the tri-snRNP and the A-complex [27].

Enzymatic interactions of LSM2

• The 27K protein can be phosphorylated in vitro by the snRNP-associated protein kinase and exhibits several isoelectric variants upon 2D gel electrophoresis [28].
• Although decreased snRNP-protein could be explained by decreased mRNA-steady state levels, another underlying mechanism might be suggested: snRNP is one of the death substrates rapidly cleaved during apoptosis by interleukin-1-beta-converting enzyme-like (ICE) proteases, which was well-documented by several groups [29].

Regulatory relationships of LSM2

• SLBP binds histone pre-mRNAs and facilitates 3'-end processing by promoting stable association of U7 snRNP with the pre-mRNA [30].
• The polypyrimidine tract binding protein (PTB) promotes exon skipping by binding to an exonic splicing silencer and inhibiting the association of U2AF and U2 snRNP with the upstream 3' splice site, without affecting recognition of the downstream 5' splice site by U1 [31].
• Furthermore, in vitro phosphorylation of TIA-1 by FAST K results in enhanced U1 snRNP recruitment [32].
• These and related data support the view that the poly-TPR Clf1p splicing factor promotes the functional integration of the U4/U6.U5 tri-snRNP particle into the U1-, U2-dependent prespliceosome [33].
• snRNP protein expression enhances the formation of Cajal bodies containing p80-coilin and SMN [34].

Other interactions of LSM2

• This suggests that SMN also functions in the assembly of the U6 snRNP in the nucleus and in the assembly of other Lsm-containing complexes [1].
• Our results reveal a new function of U2AF65: to position a DEAD box protein required for U2 snRNP binding at the pre-mRNA branchpoint region [17].
• The human 56-kD U2AF(65)-associated protein (hUAP56), a member of the DExD/H box protein family of RNA-dependent ATPases, is required for the stable binding of U2 snRNP to the pre-mRNA branchpoint [35].
• The SMN protein is tightly associated with a novel protein, SIP1, and together they form a complex with several spliceosomal snRNP proteins [8].
• It is likely that the RBD of SLBP interacts directly with both the stem-loop RNA and other processing factor(s), most likely the U7 snRNP, to facilitate histone pre-mRNA processing [36].

Analytical, diagnostic and therapeutic context of LSM2

• Further purification of CPF by buoyant density centrifugation, ion exchange, and affinity column chromatography or by gel filtration demonstrates that CPF activity resides in a ribonucleoprotein and copurifies with U11 snRNP [37].
• Here we describe the three-dimensional structure of human U1 snRNP, determined by single-particle electron cryomicroscopy at 10 A resolution [38].
• Reduced U snRNP assembly causes motor axon degeneration in an animal model for spinal muscular atrophy [3].
• Immunofluorescence staining using various snRNP-specific antisera shows complete agreement with that of their antisense snRNA oligonucleotide counterparts [39].
• Electron microscopy of the 15S U2 snRNP shows that it consists of two domains in which the characteristic features of isolated SF3b and the 12S U2 snRNP are conserved [40].

References