Biomolecular condensation of NUP98 fusion proteins drives leukemogenic gene expression

Terlecki-Zaniewicz, Stefan; Humer, Theresa; Eder, Thomas; Schmoellerl, Johannes; Heyes, Elizabeth; Manhart, Gabriele; Kuchynka, Natalie; Parapatics, Katja; Liberante, Fabio G.; Müller, André C.; Tomazou, Eleni M.; Grebien, Florian

doi:10.1038/s41594-020-00550-w

Cited by 62 publications

(70 citation statements)

References 72 publications

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“…Similar translocation and condensation of PLDs of heterogeneous nuclear ribonucleoproteins (hnRNPs) from the FET family (FUS, EWSR1, and TAF15) may be at play in other cancers [112]. Oncoproteins that drive leukemia progression analogously involve the fusion of NUP98's intrinsically disordered N terminus preferentially to C termini of other phase-separating proteins, resulting in nuclear puncta formation and altered gene expression [113]. Additionally, mutations to the tumor suppressor speckle-type POZ protein (SPOP) cause cancer in part by leading to the dissolution of SPOP from enzymatically functional condensates [114].…”

Section: Anomalies In Dna-condensate Phase Behavior In Diseasementioning

confidence: 99%

Phase separation in genome organization across evolution

Feric

Misteli

2021

Trends in Cell Biology

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Section: Anomalies In Dna-condensate Phase Behavior In Diseasementioning

confidence: 99%

Phase separation in genome organization across evolution

Feric

Misteli

2021

Trends in Cell Biology

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“…We next sought to characterize proteins responsible for MLO formation by experimental approaches. The small molecule biotinylated isoxazole (b-isox) forms microcrystals that are able to precipitate proteins that localize in RNA granules 17 as well as other MLOs 18,19 .…”

Section: Resultsmentioning

confidence: 99%

ProXs drive the formation of membraneless organelles in plants

Zhang

Peng

Liu

et al. 2021

Preprint

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Membraneless organelles (MLOs) are non-membranous structures inside cells that organize cellular space and processes. The recent discovery that MLOs can be assembled via liquid-liquid phase separation (LLPS) advanced our understanding of these structures. However, the proteins that are capable of forming MLOs are largely unknown, especially in plants. In this study, we developed a method to identify proteins that we referred as ProXs (Proteins enriched by b-isoX) in Arabidopsis. Heterologous expression in yeast cells showed that most ProXs were capable of forming MLOs autonomously. We applied this method to several model and crop species including early and higher plants. This allowed us to generate an atlas of ProXs for studying plant MLOs. Analysis of ProXs from different species revealed high degree of conservation, supporting that they play important roles in cellular functions and are positively selected during evolution. Our method will be a valuable tool to characterize novel MLOs from desired cells and the data generated in present study will be instrumental for the plant research community to investigate MLO biology.

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“…N98 fusion proteins and N98 are known to interact with DNA and chromatin and to play regulatory roles in gene expression at distinct levels [ 14 , 20 , 22 , 24 , 26 , 27 , 41 , 42 , 61 , 62 , 63 , 64 , 65 ]. Our study confirmed the bivalent association of NHA9 with the active histone modification mark H3K4me3, as well as the facultative heterochromatin mark H3K27me3 (( Figure 3 ); see also [ 65 ]).…”

Section: Discussionmentioning

confidence: 99%

The Retinoblastoma Tumor Suppressor Is Required for the NUP98-HOXA9-Induced Aberrant Nuclear Envelope Phenotype

Vaz

Fahrenkrog

2021

Cells

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Chromosomal translocations involving the nucleoporin NUP98 gene are recurrently identified in leukemia; yet, the cellular defects accompanying NUP98 fusion proteins are poorly characterized. NUP98 fusions cause changes in nuclear and nuclear envelope (NE) organization, in particular, in the nuclear lamina and the lamina associated polypeptide 2α (LAP2α), a regulator of the tumor suppressor retinoblastoma protein (RB). We demonstrate that, for NUP98-HOXA9 (NHA9), the best-studied NUP98 fusion protein, its effect(s) on nuclear architecture largely depend(s) on RB. Morphological alterations caused by the expression of NHA9 are largely diminished in the absence of RB, both in human cells expressing the human papillomavirus 16 E7 protein and in mouse embryonic fibroblasts lacking RB. We further show that NHA9 expression associates with distinct histone modification. Moreover, the pattern of trimethylation of histone H3 lysine-27 is affected by NHA9, again in an RB-dependent manner. Our results pinpoint to an unexpected interplay between NUP98 fusion proteins and RB, which may contribute to leukemogenesis.

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Biomolecular condensation of NUP98 fusion proteins drives leukemogenic gene expression

Cited by 62 publications

References 72 publications

Phase separation in genome organization across evolution

Phase separation in genome organization across evolution

ProXs drive the formation of membraneless organelles in plants

The Retinoblastoma Tumor Suppressor Is Required for the NUP98-HOXA9-Induced Aberrant Nuclear Envelope Phenotype

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