TLS and PRMT1 synergistically coactivate transcription at the survivin promoter through TLS arginine methylation

Ryu

et al. 2017

Sci Rep

Mutations in fused in sarcoma (FUS), a DNA/RNA binding protein, are associated with familial amyotrophic lateral sclerosis (ALS). However, little is known about how ALS-causing mutations alter protein-protein and protein-RNA complexes and contribute to neurodegeneration. In this study, we identified protein arginine methyltransferase 1 (PRMT1) as a protein that more avidly associates with ALS-linked FUS-R521C than with FUS-WT (wild type) or FUS-P525L using co-immunoprecipitation and LC-MS analysis. Abnormal association between FUS-R521C and PRMT1 requires RNA, but not methyltransferase activity. PRMT1 was sequestered into cytosolic FUS-R521C-positive stress granule aggregates. Overexpression of PRMT1 rescued neurite degeneration caused by FUS-R521C upon oxidative stress, while loss of PRMT1 further accumulated FUS-positive aggregates and enhanced neurite degeneration. Furthermore, the mRNA of Nd1-L, an actin-stabilizing protein, was sequestered into the FUS-R521C/PRMT1 complex. Nd1-L overexpression rescued neurite shortening caused by FUS-R521C upon oxidative stress, while loss of Nd1-L further exacerbated neurite shortening. Altogether, these data suggest that the abnormal stable complex of FUS-R521C/PRMT1/Nd1-L mRNA could contribute to neurodegeneration upon oxidative stress. Overall, our study provides a novel pathogenic mechanism of the FUS mutation associated with abnormal protein-RNA complexes upon oxidative stress in ALS and provides insight into possible therapeutic targets for this pathology.

“…1). Our LC-MS findings further supports previous reports that FUS binds to PRMT1 in mammalian cell lines and neuronal cells in vitro and in vivo 1617182223.…”

Section: Resultssupporting

confidence: 91%

Sequestration of PRMT1 and Nd1-L mRNA into ALS-linked FUS mutant R521C-positive aggregates contributes to neurite degeneration upon oxidative stress

Ryu

et al. 2017

Sci Rep

Journal of Biological Chemistry

“…2). ChIP assays revealed that although PRMT1 and PRMT4 were enriched at known target promoters (29,30), their binding to PRMT7 target promoters was unaffected in both control and PRMT7 knockdown cells. These results indicate that both of these co-activator enzymes are not involved during transcriptional derepression of PRMT7 target DNA repair genes.…”

Section: ϫ3mentioning

confidence: 99%

Protein Arginine Methyltransferase 7 Regulates Cellular Response to DNA Damage by Methylating Promoter Histones H2A and H4 of the Polymerase δ Catalytic Subunit Gene, POLD1

Karkhanis

Wang

Tae

et al. 2012

117

140

Background: PRMT7 symmetrically methylates histones H2A and H4, and modulates cellular response to DNA damage. Results: PRMT7 interacts with BRG1-hSWI/SNF, targets H2AR3 and H4R3, and represses expression of POLD1. Conclusion: PRMT7 regulates response to DNA damage and confers resistance to DNA-damaging agents. Significance: Understanding how PRMT7 regulates response to genotoxic stress will clarify how cancer cells become drug-resistant.

Progress in Neurobiology

“…Although it has not been reported that TDP-43 is methylated, previous work has shown that FUS is highly methylated at most of its 37 arginine residues (Du et al, 2011; Rappsilber et al, 2003), and the protein arginine transferases (PRMT) 1 and 8 have been demonstrated to interact and catalyze arginine methylation of FUS. PRMT was found to methylate both wild-type (WT) and FUS FALS mutants at a comparable overall level, even when the mutation occurred at arginine residues (Jackel et al, 2015).…”

Section: Neurotoxicity Of Tdp-43/ Fusmentioning

confidence: 99%

“…PRMT was found to methylate both wild-type (WT) and FUS FALS mutants at a comparable overall level, even when the mutation occurred at arginine residues (Jackel et al, 2015). Methylation enhances the toxicity of ALS-associated FUS mutants by regulating their subcellular localization as well as the formation of SGs (Dormann et al, 2012; Du et al, 2011; Scaramuzzino et al, 2013; Tradewell et al, 2012), although it is controversial whether or not methyltransferase activity is involved in the incorporation of FUS into SGs (Baron et al, 2013; Sama et al, 2013). Insights into how arginine methylation affects the subcellular localization of FUS have been given by Hass and colleagues (Dormann et al, 2012), who found that PRMT1-mediated arginine methylation within the RGG3 domain (but not PY-NLS) is necessary and sufficient to restore nuclear import of mutant FUS upon inhibition of methyltransferase activity by methylation inhibitor AdOx.…”

Section: Neurotoxicity Of Tdp-43/ Fusmentioning

confidence: 99%

TDP-43/FUS in motor neuron disease: Complexity and challenges

Guerrero

Wang

Mitra

et al. 2016

105

125

Amyotrophic lateral sclerosis (ALS), a common motor neuron disease affecting two per 100,000 people worldwide, encompasses at least five distinct pathological subtypes, including, ALS-SOD1, ALS-C9orf72, ALS-TDP-43, ALS-FUS and Guam-ALS. The etiology of a major subset of ALS involves toxicity of the TAR DNA-binding protein-43 (TDP-43). A second RNA/DNA binding protein, fused in sarcoma/translocated in liposarcoma (FUS/TLS) has been subsequently associated with about 1% of ALS patients. While mutations in TDP-43 and FUS have been linked to ALS, the key contributing molecular mechanism(s) leading to cell death are still unclear. One unique feature of TDP-43 and FUS pathogenesis in ALS is their nuclear clearance and simultaneous cytoplasmic aggregation in affected motor neurons. Since the discoveries in the last decade implicating TDP-43 and FUS toxicity in ALS, a majority of studies have focused on their cytoplasmic aggregation and disruption of their RNA-binding functions. However, TDP-43 and FUS also bind to DNA, although the significance of their DNA binding in disease-affected neurons has been less investigated. A recent observation of accumulated genomic damage in TDP-43 and FUS-linked ALS and association of FUS with neuronal DNA damage repair pathways indicate a possible role of deregulated DNA binding function of TDP-43 and FUS in ALS. In this review, we discuss the different ALS disease subtypes, crosstalk of etiopathologies in disease progression, available animal models and their limitations, and recent advances in understanding the specific involvement of RNA/DNA binding proteins, TDP-43 and FUS, in motor neuron diseases.