Regulation of transcription termination by FUS and TDP-43

Zhao, Dorothy Yanling; Ni, Zuyao; Pu, Shuye; Schmitges, Frank W.; Braunschweig, Ulrich; Blencowe, Benjamin J.; Greenblatt, Jack

doi:10.1101/788778

Cited by 3 publications

(3 citation statements)

References 72 publications

(86 reference statements)

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“…In addition to its role in snRNP biogenesis, symmetrical dimethylation by PRMT5 of the carboxyl-terminal domain of Polymerase II in arginine R1810 has been reported to facilitate the recruitment of SMN and senataxin to form a complex responsible for R-loops resolution during transcriptional termination (Figure 2; Zhao et al, 2016).…”

Section: Methylationmentioning

confidence: 99%

SMN post-translational modifications in spinal muscular atrophy

Riboldi

Faravelli²,

Rinchetti³

et al. 2023

Front. Cell. Neurosci.

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Since its first identification as the gene responsible for spinal muscular atrophy (SMA), the range of survival motor neuron (SMN) protein functions has increasingly expanded. This multimeric complex plays a crucial role in a variety of RNA processing pathways. While its most characterized function is in the biogenesis of ribonucleoproteins, several studies have highlighted the SMN complex as an important contributor to mRNA trafficking and translation, axonal transport, endocytosis, and mitochondria metabolism. All these multiple functions need to be selectively and finely modulated to maintain cellular homeostasis. SMN has distinct functional domains that play a crucial role in complex stability, function, and subcellular distribution. Many different processes were reported as modulators of the SMN complex activities, although their contribution to SMN biology still needs to be elucidated. Recent evidence has identified post-translational modifications (PTMs) as a way to regulate the pleiotropic functions of the SMN complex. These modifications include phosphorylation, methylation, ubiquitination, acetylation, sumoylation, and many other types. PTMs can broaden the range of protein functions by binding chemical moieties to specific amino acids, thus modulating several cellular processes. Here, we provide an overview of the main PTMs involved in the regulation of the SMN complex with a major focus on the functions that have been linked to SMA pathogenesis.

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Section: Methylationmentioning

confidence: 99%

SMN post-translational modifications in spinal muscular atrophy

Riboldi

Faravelli²,

Rinchetti³

et al. 2023

Front. Cell. Neurosci.

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“…Co-IPs were performed as described previously (37,38). Cell pellets were lysed in lysis buffer (140mM NaCl, 10mM Tris pH 7.6-8.0, 1% Triton X-100, 0.1% sodium deoxy-cholate, 1mM EDTA) containing protease inhibitors.…”

Section: Co-immunoprecipitations (Co-ips)mentioning

confidence: 99%

KRAB Zinc Finger protein Znf684 interacts with Nxf1 to regulate mRNA export

Nitoiu

Nabeel‐Shah

Farhangmehr

et al. 2021

Preprint

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Cys2His2 (C2H2) type zinc finger (ZnF) proteins constitute a large class of proteins that are generally considered to be DNA-binding transcription factors. Using affinity purification followed by mass spectrometry, as well as reciprocal co-immunoprecipitation experiments, we determined that the C2H2-ZnF protein Znf684 interacts physically with several proteins involved in mRNA export, including Nxf1 and Alyref. We show that Znf684 binds directly to specific mRNAs in vivo and has an RNA-binding profile similar to those of Nxf1 and Alyref, suggesting a role in mRNA export regulation. Immunofluorescence microscopy (IF) experiments revealed that Znf684 localizes to both the nucleus and cytoplasm. Using cellular fractionation experiments, we demonstrate that overexpression of Znf684 negatively impacts the export of SMAD3 and other target mRNAs. Taken together, our results suggest that Znf684 regulates the export of a subset of transcripts through physical interactions with Nxf1 and specific target mRNAs.

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“…When FUS is missing, RNAP2 accumulates at the transcription start site and causes a shift in mRNA transcripts expression toward early polyadenylation sites [69]. Moreover, defects in FUS and TDP-43 recruitment influence RNAPII termination and determine R-loop (DNA:RNA hybrids) accumulation, leading to elevated DNA damage at transcription terminators [70]. Also, the recently described ALS-associated gene MATR3 interacts with POLR2A, POLR2B, and POLR2C at the early steps of transcription [71].…”

Section: Rna Polymerase II Core Complexmentioning

confidence: 99%

Splicing Players Are Differently Expressed in Sporadic Amyotrophic Lateral Sclerosis Molecular Clusters and Brain Regions

Cognata

Gentile

Aronica

et al. 2020

Cells

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Splicing is a tightly orchestrated process by which the brain produces protein diversity over time and space. While this process specializes and diversifies neurons, its deregulation may be responsible for their selective degeneration. In amyotrophic lateral sclerosis (ALS), splicing defects have been investigated at the singular gene level without considering the higher-order level, involving the entire splicing machinery. In this study, we analyzed the complete spectrum (396) of genes encoding splicing factors in the motor cortex (41) and spinal cord (40) samples from control and sporadic ALS (SALS) patients. A substantial number of genes (184) displayed significant expression changes in tissue types or disease states, were implicated in distinct splicing complexes and showed different topological hierarchical roles based on protein–protein interactions. The deregulation of one of these splicing factors has a central topological role, i.e., the transcription factor YBX1, which might also have an impact on stress granule formation, a pathological marker associated with ALS.

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Regulation of transcription termination by FUS and TDP-43

Cited by 3 publications

References 72 publications

SMN post-translational modifications in spinal muscular atrophy

SMN post-translational modifications in spinal muscular atrophy

KRAB Zinc Finger protein Znf684 interacts with Nxf1 to regulate mRNA export

Splicing Players Are Differently Expressed in Sporadic Amyotrophic Lateral Sclerosis Molecular Clusters and Brain Regions

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