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MacKenzie, Alex

doi:10.1038/82983

Cited by 11 publications

(3 citation statements)

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“…It is known that spliceosomal snRNP assembly, at least in higher eukaryotes, requires interactions with the SMN protein, which appears to play a role in guiding the correct associations of different Sm hetero-complexes (43)(44)(45). The results of this study clearly show that Sm/Lsm protein-protein interactions are not limited to highly specific hetero-associations.…”

Section: Discussionmentioning

confidence: 99%

Homomeric Ring Assemblies of Eukaryotic Sm Proteins Have Affinity for Both RNA and DNA

Collins

Cubeddu

Naidoo

et al. 2003

Journal of Biological Chemistry

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Sm and Sm-like proteins are key components of small ribonucleoproteins involved in many RNA and DNA processing pathways. In eukaryotes, these complexes contain seven unique Sm or Sm-like (Lsm) proteins assembled as hetero-heptameric rings, whereas in Archaea and bacteria six or seven-membered rings are made from only a single polypeptide chain. Here we show that single Sm and Lsm proteins from yeast also have the capacity to assemble into homo-oligomeric rings. Formation of homo-oligomers by the spliceosomal small nuclear ribonucleoprotein components SmE and SmF preclude hetero-interactions vital to formation of functional small nuclear RNP complexes in vivo. To better understand these unusual complexes, we have determined the crystal structure of the homomeric assembly of the spliceosomal protein SmF. Like its archaeal/bacterial homologs, the SmF complex forms a homomeric ring but in an entirely novel arrangement whereby two heptameric rings form a co-axially stacked dimer via interactions mediated by the variable loops of the individual SmF protein chains. Furthermore, we demonstrate that the homomeric assemblies of yeast Sm and Lsm proteins are capable of binding not only to oligo(U) RNA but, in the case of SmF, also to oligo(dT) singlestranded DNA.

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Section: Discussionmentioning

confidence: 99%

Homomeric Ring Assemblies of Eukaryotic Sm Proteins Have Affinity for Both RNA and DNA

Collins

Cubeddu

Naidoo

et al. 2003

Journal of Biological Chemistry

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“…The protein ZK1127.10 as described in Chapter 1 (which is involved in H 2 S and SO 2 metabolism) is also found to be a SMN-1 interacting protein, identified by a yeast two-hybrid screen [271]. It is likely that both F08F8.9 and ZK1127.10 are involved in metabolic pathway of SO 2 and certain mutations in F08F8.9 cause resistance to SO 2 exposure, potentially by an increase of the catabolic rate.…”

Section: So 2 Resistance: F08f89mentioning

confidence: 99%

“…F08F8.9 has also been shown to have direct interaction with the survival motor neuron (SMN) gene [270], to participate in assembly of the splicing apparatus (spliceosome) and in pre-mRNA splicing, and to contribute to transcriptional regulation [271]. The protein ZK1127.10 as described in Chapter 1 (which is involved in H 2 S and SO 2 metabolism) is also found to be a SMN-1 interacting protein, identified by a yeast two-hybrid screen [271].…”

Section: So 2 Resistance: F08f89mentioning

confidence: 99%

Developing high-throughput methods for C. elegans to better understand the newly discovered gasotransmitter sulfur dioxide

Mathew¹

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Sulfur Dioxide (SO 2 ) is the most recently discovered gasotransmitter. As a result there is a significant gap in the literature compared to the other established gasotransmitters which have had several decades of research. Initially, SO 2 was thought to be a toxic air pollutant and byproduct from the metabolism of sulphur containing amino acids. It is thus important to understand its mechanism of action and molecular targets of SO 2 . The pathways for metabolism of sulfur containing gasotransmitters (hydrogen sulfide and sulfur dioxide) in lower organisms was previously unknown. My thesis goal is to gain a better understanding of the function and metabolism of SO 2 . To better elucidate this function I have used the eukaryotic model organisms; Saccharomyces cerevisiae (S. cerevisiae) and Caenorhabditis elegans (C. elegans).Two high-throughput methods were developed as part of this research to improve detail and accuracy of analysis in C. elegans. The first method developed was WormScan, which allowed for automatic whole organism phenotyping. The second method developed was pHi nanoparticles, to enable the characterization of intracellular pH (pHi). These two C. elegans methods were published in PLOS ONE, 2012 and Analytical Biochemistry, 2014. WormScan is based on an affordable consumer grade flatbed scanner that facilitates the quantification of the four main toxicological endpoints of C. elegans and greatly reduces the user bias associated with manual counting. The light intensity produced by the scanner was sufficient to cause negative phototaxis equivalent to a physical stimulus for mortality determination. The affordability and high-throughput nature of WormScan also enable high-throughput whole animal drug screening in C. elegans. The pHi nanoparticles were generated through a modified Stöber synthesis and easily calibrated externally to the C. elegans. The nanoparticles were taken up during feeding, and found to bypass the selective intestinal uptake and translocate to the primary organs and secondary organs of the reproductive tract. This was the first diagnostic use of nanoparticles in C. elegans.It was found that the hypoxia-inducible factor-1 (hif-1) transcription factor was required in order for C. elegans to survive exposure to SO 2 . HIF-1 is a regulator of both pHi homeostasis and metabolic rate. When C. elegans are exposed to a non-lethal concentration of SO 2 , it induced a reversible state of suspended animation, a condition that is characterized by metabolic suppression. A physiologically relevant drop of 0.15 pH units was observed in response to SO 2 exposure. Where such a decrease in pHi is a characteristic of reduced metabolism.II A forward genetic screen was carried out in C. elegans to identify mutations that conferred resistance to SO 2 . A resistance mutation was mapped to a region of Chromosome III using an as yet unpublished high-throughput technique (Mip-Map). Together with whole genome sequencing the gene F08F8.9 causing resistance was identified. The F08F8.9 gene is hom...

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A novel mutation at the N-terminal of SMN Tudor domain inhibits its interaction with target proteins

et al. 2007

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Although most patients with spinal muscular atrophy (SMA) are homozygous for deletion of the SMN1 gene, some patients bear one SMN1 copy with a subtle mutation. Detection of such an intragenic mutation may be helpful not only in confirming diagnosis but also in elucidating functional domains of the SMN protein. In this study, we identified a novel mutation in SMN1 of two Japanese patients with type I SMA. DHPLC and sequencing analysis revealed that they harbored a point mutation in SMN1 exon 3, 275G > C, leading to tryptophan-to-serine substitution at amino acid 92 (W92S) at the Nterminal of SMN Tudor domain. In-vitro protein binding assays showed that the mutation severely reduced interaction of the domain with SmB protein and fibrillarin, suggesting that it impairs the critical function of SMN. In conclusion, we reported here that a novel mutation, W92S, in the Tudor domain affects the interaction of SMN with the target proteins.

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Cited by 11 publications

References 1 publication

Homomeric Ring Assemblies of Eukaryotic Sm Proteins Have Affinity for Both RNA and DNA

Homomeric Ring Assemblies of Eukaryotic Sm Proteins Have Affinity for Both RNA and DNA

Developing high-throughput methods for C. elegans to better understand the newly discovered gasotransmitter sulfur dioxide

A novel mutation at the N-terminal of SMN Tudor domain inhibits its interaction with target proteins

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