Chromosomal instability by mutations in a novel specificity factor of the minor spliceosome

Wolf, Bas de; Oghabian, Ali; Akinyi, Maureen Veronica; Hanks, Sandra; Tromer, Eelco C.; Hooff, Jolien van; Voorthuijsen, Lisa van; Rooijen, Laura E van; Verbeeren, Jens; Uijttewaal, Esther C. H.; Baltissen, Marijke P; Yost, Shawn; Piloquet, Philippe; Vermeulen, Michiel; Snel, Berend; Isidor, Bertrand; Rahman, Nazneen; Frilander, Mikko J.; Kops, Geert J.P.L.

doi:10.1101/2020.08.06.239418

Cited by 3 publications

(3 citation statements)

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“…Such systems are often lost in yeast. These observations fit with notable examples from the WASH complex and cilium [ 8 , 9 , 11 ], or proteins with great success in predicting its components like the minor spliceosome [ 5 ] and RNAi machinery genes including Dicer and Argonaute [ 32 ]. These biological patterns should explain the very strong signal found by studies such as [ 9 , 11 ].…”

Section: Discussionsupporting

confidence: 69%

“…Phylogenetic profiling is a seemingly straightforward method proven to be a valuable alternative resource for studying functional relationships between proteins. Recently the method has played an integral part in identifying the cellular functional role of CENATAC that is a key player in a rare aneuploidy condition in humans [ 5 ], identifying eukaryotic reproduction genes [ 6 ], and identifying eukaryotic novel recombination repair genes [ 7 ].…”

Section: Introductionmentioning

confidence: 99%

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Phylogenetic profiling in eukaryotes: The effect of species, orthologous group, and interactome selection on protein interaction prediction

2022

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Phylogenetic profiling in eukaryotes is of continued interest to study and predict the functional relationships between proteins. This interest is likely driven by the increased number of available diverse genomes and computational methods to infer orthologies. The evaluation of phylogenetic profiles has mainly focussed on reference genome selection in prokaryotes. However, it has been proven to be challenging to obtain high prediction accuracies in eukaryotes. As part of our recent comparison of orthology inference methods for eukaryotic genomes, we observed a surprisingly high performance for predicting interacting orthologous groups. This high performance, in turn, prompted the question of what factors influence the success of phylogenetic profiling when applied to eukaryotic genomes. Here we analyse the effect of species, orthologous group and interactome selection on protein interaction prediction using phylogenetic profiles. We select species based on the diversity and quality of the genomes and compare this supervised selection with randomly generated genome subsets. We also analyse the effect on the performance of orthologous groups defined to be in the last eukaryotic common ancestor of eukaryotes to that of orthologous groups that are not. Finally, we consider the effects of reference interactome set filtering and reference interactome species. In agreement with other studies, we find an effect of genome selection based on quality, less of an effect based on genome diversity, but a more notable effect based on the amount of information contained within the genomes. Most importantly, we find it is not merely selecting the correct genomes that is important for high prediction performance. Other choices in meta parameters such as orthologous group selection, the reference species of the interaction set, and the quality of the interaction set have a much larger impact on the performance when predicting protein interactions using phylogenetic profiles. These findings shed light on the differences in reported performance amongst phylogenetic profiles approaches, and reveal on a more fundamental level for which types of protein interactions this method has most promise when applied to eukaryotes.

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Section: Discussionsupporting

confidence: 69%

Section: Introductionmentioning

confidence: 99%

Phylogenetic profiling in eukaryotes: The effect of species, orthologous group, and interactome selection on protein interaction prediction

2022

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“…S2.3D). AR45, an AR splice variant known to heterodimerize with the full-length version, and ZRSR2, which is known to interact with the MiS 33,34 were used as positive controls.…”

Section: D Iv)mentioning

confidence: 99%

Minor intron splicing efficiency increases with the development of lethal prostate cancer

Augspach

Drake

Roma

et al. 2021

Preprint

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Here we explored the role of minor spliceosome (MiS) function and minor intron-containing gene (MIG) expression in prostate cancer (PCa). We show MIGs are enriched as direct interactors of cancer-causing genes and their expression discriminates PCa progression. Increased expression of MiS U6atac snRNA, including others, and 6x more efficient minor intron splicing was observed in castration-resistant PCa (CRPC) versus primary PCa. Notably, androgen receptor signalling influenced MiS activity. Inhibition of MiS through siU6atac in PCa caused minor intron mis-splicing and aberrant expression of MIG transcripts and encoded proteins, which enriched for MAPK activity, DNA repair and cell cycle. Single cell-RNAseq confirmed cell cycle defects and lineage dependency on the MiS from primary to CRPC and neuroendocrine PCa. siU6atac was ~50% more efficient in lowering tumor burden of CRPC cells and organoids versus current state-of-the-art combination therapy. In all, MiS is a strong therapeutic target for lethal PCa and potentially other cancers.

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Phylogenetic profiling in eukaryotes: The effect of species, orthologous group, and interactome selection on protein interaction prediction

Deutekom

Dam

Snel

2021

Preprint

Self Cite

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Phylogenetic profiling in eukaryotes is of continued interest to study and predict the functional relationships between proteins. This interest is likely driven by the increased number of available diverse genomes and computational methods to infer orthologies. The evaluation of phylogenetic profiles has mainly focussed on reference genome selection in prokaryotes. However, it has been proven to be challenging to obtain high prediction accuracies in eukaryotes. As part of our recent comparison of orthology inference methods for eukaryotic genomes, we observed a surprisingly high performance for predicting interacting orthologous groups. This high performance, in turn, prompted the question of what factors influence the success of phylogenetic profiling when applied to eukaryotic genomes.Here we analyse the effect of species, orthologous group and interactome selection on protein interaction prediction using phylogenetic profiles. We select species based on the diversity and quality of the genomes and compare this supervised selection with randomly generated genome subsets. We also analyse the effect on the performance of orthologous groups defined to be in the last eukaryotic common ancestor of eukaryotes to that of orthologous groups that are not. Finally, we consider the effects of reference interactome set filtering and reference interactome species.In agreement with other studies, we find an effect of genome selection based on quality, less of an effect based on genome diversity, but a more notable effect based on the amount of information contained within the genomes. Most importantly, we find it is not merely selecting the correct genomes that is important for high prediction performance. Other choices in meta parameters such as orthologous group selection, the reference species of the interaction set, and the quality of the interaction set have a much larger impact on the performance when predicting protein interactions using phylogenetic profiles. These findings shed light on the differences in reported performance amongst phylogenetic profiles approaches, and reveal on a more fundamental level for which types of protein interactions this method has most promise when applied to eukaryotes.

show abstract

Chromosomal instability by mutations in a novel specificity factor of the minor spliceosome

Cited by 3 publications

References 85 publications

Phylogenetic profiling in eukaryotes: The effect of species, orthologous group, and interactome selection on protein interaction prediction

Phylogenetic profiling in eukaryotes: The effect of species, orthologous group, and interactome selection on protein interaction prediction

Minor intron splicing efficiency increases with the development of lethal prostate cancer

Phylogenetic profiling in eukaryotes: The effect of species, orthologous group, and interactome selection on protein interaction prediction

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