FUsed in Sarcoma Is a Novel Regulator of Manganese Superoxide Dismutase Gene Transcription

Dhar, Subhra; Zhang, Jia Yu; Gál, József; Xu, Yong; Liu, Miao; Lynn, Bert C.; Zhu, Haining; Kasarskis, Edward J.; Clair, Daret K. St.

doi:10.1089/ars.2012.4984

Cited by 24 publications

(25 citation statements)

References 60 publications

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“…The observation that FUS binds to active chromatin is consistent with earlier reports that FUS can regulate gene transcription (21,22). This study shows that the truncated FUS 165-526 lacking the N-terminal QGSY-rich region is incapable of binding to chromatin.…”

Section: Chromatin Binding Of Fus Is Required For Its Function Of Regsupporting

confidence: 92%

“…This conclusion is also supported by a previous report that knockdown of FUS in mouse brain decreased expression of hundreds of genes (23). The requirement of chromatin binding for its gene transcription activation, along with the finding that ALS mutations impair chromatin binding, provides a mechanism for the previous observation that the ALS mutant FUS lost its transcription activation capability (21).…”

Section: Chromatin Binding Of Fus Is Required For Its Function Of Regsupporting

confidence: 79%

“…The ALS mutations disrupt this assembly and chromatin binding, which could result in several potentially adverse consequences. The ALS mutations R521G and R495X, which significantly decreased FUS chromatin binding, were found to impair the gene transcription of a critical mitochondrial antioxidant protein MnSOD in our previous studies (21). FUS chromatin binding may also be crucial for DNA damage repair.…”

Section: Chromatin Binding Of Fus Is Required For Its Function Of Regmentioning

confidence: 79%

“…FUS has been shown to regulate gene transcription (20)(21)(22) and alternative splicing (20,23). We next tested the relationship between chromatin binding and FUS function in gene transcription and alternative splicing using the full-length FUS and the truncated FUS 165-526, which is deficient in chromatin binding.…”

Section: The Role Of Fus Chromatin Binding In Transcription Regulatiomentioning

confidence: 99%

“…We used the manganese superoxide dismutase (MnSOD) reporter assay (Fig. S4A) because FUS was shown to activate the transcription of MnSOD (21). The fulllength FUS or FUS 165-526 construct along with a reporter plasmid carrying the MnSOD promoter were transfected into HEK cells.…”

Section: The Role Of Fus Chromatin Binding In Transcription Regulatiomentioning

confidence: 99%

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Self-assembled FUS binds active chromatin and regulates gene transcription

Yang

Gál

Chen

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease. Fused in sarcoma (FUS) is a DNA/RNA binding protein and mutations in FUS cause a subset of familial ALS. Most ALS mutations are clustered in the C-terminal nuclear localization sequence of FUS and consequently lead to the accumulation of protein inclusions in the cytoplasm. It remains debatable whether loss of FUS normal function in the nucleus or gain of toxic function in the cytoplasm plays a more critical role in the ALS etiology. Moreover, the physiological function of FUS in the nucleus remains to be fully understood. In this study, we found that a significant portion of nuclear FUS was bound to active chromatin and that the ALS mutations dramatically decreased FUS chromatin binding ability. Functionally, the chromatin binding is required for FUS transcription activation, but not for alternative splicing regulation. The N-terminal QGSY (glutamine-glycine-serine-tyrosine)-rich region (amino acids 1-164) mediates FUS self-assembly in the nucleus of mammalian cells and the self-assembly is essential for its chromatin binding and transcription activation. In addition, RNA binding is also required for FUS self-assembly and chromatin binding. Together, our results suggest a functional assembly of FUS in the nucleus under physiological conditions, which is different from the cytoplasmic inclusions. The ALS mutations can cause loss of function in the nucleus by disrupting this assembly and chromatin binding. FUS is a multifunctional protein and has been reported to play a role in various aspects of RNA metabolism (6), including transcription regulation and alternative splicing. FUS was initially identified in liposarcomas as part of a fusion protein (7,8) in which the N-terminal domain of FUS (amino acid 1-266) is recombined to transcription factor CHOP at its N terminus. The FUS-CHOP fusion protein activates the transcription of oncogenes and promotes tumorigenesis (9, 10). In familial ALS, most mutations are clustered in the C-terminal nuclear localization sequence (NLS) of FUS and consequently cause the mislocalization of FUS protein from the nucleus to the cytoplasm and the accumulation of protein inclusions (11-13). Such observations suggest two potential disease-causing mechanisms: loss of FUS normal function in the nucleus and gain of toxic function in the cytoplasm. It remains to be determined which mechanism plays a more critical role in ALS etiology and the two mechanisms are not necessarily exclusive of each other.Cytoplasmic FUS inclusions resemble stress granules, indicated by colocalization of FUS with different stress granule components (11,12). Stress granules are temporary cellular structures containing RNAs and proteins from suspended translation apparatus (14). Stress granule formation promotes cell survival under stressed conditions by redistributing translation resources. Compromised stress granule response in the presence of FUS mutants is considered a contributing factor to motor neuron dysfunction (15).Although t...

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Section: Chromatin Binding Of Fus Is Required For Its Function Of Regsupporting

confidence: 92%

Section: Chromatin Binding Of Fus Is Required For Its Function Of Regsupporting

confidence: 79%

Section: Chromatin Binding Of Fus Is Required For Its Function Of Regmentioning

confidence: 79%

Section: The Role Of Fus Chromatin Binding In Transcription Regulatiomentioning

confidence: 99%

Section: The Role Of Fus Chromatin Binding In Transcription Regulatiomentioning

confidence: 99%

See 3 more Smart Citations

Self-assembled FUS binds active chromatin and regulates gene transcription

Yang

Gál

Chen

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

128

122

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ALS mutant SOD1 interacts with G3BP1 and affects stress granule dynamics

et al. 2016

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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease. Mutations in Cu/Zn superoxide dismutase (SOD1) are responsible for approximately 20 % of the familial ALS cases. ALS-causing SOD1 mutants display a gain-of-toxicity phenotype, but the nature of this toxicity is still not fully understood. The Ras GTPase-activating protein-binding protein G3BP1 plays a critical role in stress granule dynamics. Alterations in the dynamics of stress granules have been reported in several other forms of ALS unrelated to SOD1. To our surprise, the mutant G93A SOD1 transgenic mice exhibited pathological cytoplasmic inclusions that co-localized with G3BP1-positive granules in spinal cord motor neurons. The co-localization was also observed in fibroblast cells derived from familial ALS patient carrying SOD1 mutation L144F. Mutant SOD1, unlike wild-type SOD1, interacted with G3BP1 in an RNA-independent manner. Moreover, the interaction is specific for G3BP1 since mutant SOD1 showed little interaction with four other RNA-binding proteins implicated in ALS. The RNA-binding RRM domain of G3BP1 and two particular phenylalanine residues (F380 and F382) are critical for this interaction. Mutant SOD1 delayed the formation of G3BP1- and TIA1-positive stress granules in response to hyperosmolar shock and arsenite treatment in N2A cells. In summary, the aberrant mutant SOD1–G3BP1 interaction affects stress granule dynamics, suggesting a potential link between pathogenic SOD1 mutations and RNA metabolism alterations in ALS.Electronic supplementary materialThe online version of this article (doi:10.1007/s00401-016-1601-x) contains supplementary material, which is available to authorized users.

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Tau drives translational selectivity by interacting with ribosomal proteins

et al. 2019

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There is a fundamental gap in understanding the consequences of tau–ribosome interactions. Tau oligomers and filaments hinder protein synthesis in vitro, and they associate strongly with ribosomes in vivo. Here, we investigated the consequences of tau interactions with ribosomes in transgenic mice, in cells, and in human brain tissues to identify tau as a direct modulator of ribosomal selectivity. First, we performed microarrays and nascent proteomics to measure changes in protein synthesis. Using regulatable rTg4510 tau transgenic mice, we determined that tau expression differentially shifts both the transcriptome and the nascent proteome, and that the synthesis of ribosomal proteins is reversibly dependent on tau levels. We further extended these results to human brains and found that tau pathologically interacts with ribosomal protein S6 (rpS6 or S6), a crucial regulator of translation. Consequently, protein synthesis under translational control of rpS6 was reduced under tauopathic conditions in Alzheimer’s disease brains. Our data establish tau as a driver of RNA translation selectivity. Moreover, since regulation of protein synthesis is critical for learning and memory, aberrant tau–ribosome interactions in disease could explain the linkage between tauopathies and cognitive impairment.Electronic supplementary materialThe online version of this article (10.1007/s00401-019-01970-9) contains supplementary material, which is available to authorized users.

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FUsed in Sarcoma Is a Novel Regulator of Manganese Superoxide Dismutase Gene Transcription

Cited by 24 publications

References 60 publications

Self-assembled FUS binds active chromatin and regulates gene transcription

Self-assembled FUS binds active chromatin and regulates gene transcription

ALS mutant SOD1 interacts with G3BP1 and affects stress granule dynamics

Tau drives translational selectivity by interacting with ribosomal proteins

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