RNA-binding proteins TDP-43 and FUS promote R-loop resolution and regulate transcription termination

Topic: Brain proteins, microglia and lab models

TDP-43 and FUS are RNA-binding proteins involved in the regulation of diverse RNA-processing events and have been strongly implicated in neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). We have previously demonstrated the role of symmetrical dimethylation (me2s) of a conserved arginine residue (R1810 in human POLR2A) in the C-terminal domain (CTD) of RNA polymerase II (RNAPII), which facilitates the recruitment of the Tudor domain-containing protein SMN to resolve R-loops at transcriptional termination sites. Here, we demonstrate that TDP-43 and FUS contribute to transcription termination through the R1810me2s-SMN pathway. Our data show that TDP-43-and to a lesser extent, FUS-are recruited to chromatin via this pathway, and that disruption of their recruitment leads to defective RNAPII termination. This impairment results in the accumulation of R-loops and elevated DNA damage to gene terminators. Using transcriptome-wide analyses, we further show that TDP-43 RNA-binding sites are highly correlated with regions of R-loop formation. Importantly, we find that the RNA-binding activity of TDP-43 is essential for its role in resolving R-loops and promoting efficient transcription termination. These findings establish a mechanistic link between TDP-43/FUS, R-loop resolution, and transcription termination, providing new insights into how their dysfunction may drive genome instability and contribute to the pathogenesis of ALS and FTD.

@article{zhao2026-41796799,
  author  = {Zhao, Dorothy Yanling and Nabeel‐Shah, Syed and Ni, Zuyao and Pu, Shuye and Zhong, Guoqing and Schmitges, Frank W. and Braunschweig, Ulrich and Blencowe, Benjamin J. and others},
  title   = {{RNA-binding proteins TDP-43 and FUS promote R-loop resolution and regulate transcription termination}},
  journal = {Journal of Biological Chemistry},
  year    = {2026},
  doi     = {10.1016/j.jbc.2026.111348},
  pmid    = {41796799},
  url     = {https://doi.org/10.1016/j.jbc.2026.111348}
}

Key findings

• We have previously demonstrated the role of symmetrical dimethylation (me2s) of a conserved arginine residue (R1810 in human POLR2A) in the C-terminal domain (CTD) of RNA polymerase II (RNAPII), which facilitates the recruitment of the Tudor domain-containing protein SMN to resolve R-loops at transcriptional termination sites.
• This impairment results in the accumulation of R-loops and elevated DNA damage to gene terminators.
• These findings establish a mechanistic link between TDP-43/FUS, R-loop resolution, and transcription termination, providing new insights into how their dysfunction may drive genome instability and contribute to the pathogenesis of ALS and FTD.

Why it matters

This laboratory study shows that TDP-43 and FUS contribute to transcription termination through the R1810me2s-SMN pathway, and that disruption of their recruitment leads to defective RNA polymerase II termination, R-loop accumulation and DNA damage. It establishes a mechanistic link between these proteins and transcription termination but does not test any treatment, cure or prevention.

Study details

• Evidence strengthLow

Read the original

• DOI: 10.1016/j.jbc.2026.111348
• PubMed: 41796799
• Original source →
• Free full text: Journal of Biological Chemistry →

Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).

Studies this one cites

Referenced by this study and also in the alzhub library, so you can read them here.

• TDP-43 Mutations in Familial and Sporadic Amyotrophic Lateral Sclerosis Science · 2008-02-28 · usefulness score 64/100 · Disease mechanisms
• Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis Science (New York, N.Y.) · 2006-10-01 · usefulness score 62/100 · Lewy body dementia
• The C9orf72 GGGGCC repeat is translated into aggregating dipeptide-repeat proteins in FTLD/ALS Science (New York, N.Y.) · 2013-02-07 · usefulness score 59/100 · Lewy body dementia
• TDP-43 and FUS in amyotrophic lateral sclerosis and frontotemporal dementia The Lancet. Neurology · 2010-10-01 · usefulness score 57/100 · Lewy body dementia
• C9orf72 nucleotide repeat structures initiate molecular cascades of disease Nature · 2014-03-05 · usefulness score 57/100 · Lewy body dementia
• Divergent roles of ALS-linked proteins FUS/TLS and TDP-43 intersect in processing long pre-mRNAs Nature neuroscience · 2012-09-30 · usefulness score 56/100 · Lewy body dementia
• Interaction of FUS and HDAC1 regulates DNA damage response and repair in neurons Nature neuroscience · 2013-09-15 · usefulness score 55/100 · Lewy body dementia
• ALS-associated fused in sarcoma (FUS) mutations disrupt Transportin-mediated nuclear import The EMBO journal · 2010-07-06 · usefulness score 53/100 · Lewy body dementia
• The role of TDP-43 propagation in neurodegenerative diseases: integrating insights from clinical and experimental studies Experimental & molecular medicine · 2020-10-13 · usefulness score 51/100 · Lewy body dementia
• The genetics and neuropathology of amyotrophic lateral sclerosis Acta neuropathologica · 2012-08-02 · usefulness score 50/100 · Lewy body dementia

Related studies in Brain tissue and pathology

• TDP-43 and FUS RNA-binding proteins bind distinct sets of cytoplasmic messenger RNAs and differently regulate their post-transcriptional fate in motoneuron-like cells The Journal of biological chemistry · 2012-03-16 · usefulness score 47/100
• PARylation regulates stress granule dynamics, phase separation, and neurotoxicity of disease-related RNA-binding proteins Cell research · 2019-02-06 · usefulness score 49/100
• DCPS modulates TDP-43-linked neurodegeneration through P-body-mediated RNA decay Neuron · 2026-03-09 · usefulness score 45/100
• TDP-43 oxidation and PP1 crosstalk at RNA granule-mitochondria contact sites Nature Communications · 2026-06-05 · usefulness score 41/100
• Single-nucleus RNA sequencing reveals GABAergic vulnerability and reactive gliosis driven by loss of TDP-43 iScience · 2025-10-17 · usefulness score 34/100
• FUS pathology defines the majority of tau- and TDP-43-negative frontotemporal lobar degeneration Acta neuropathologica · 2010-05-20 · usefulness score 53/100

Also tagged “tdp-43”

1,150 studies in the library carry the topic tag “tdp-43”; these are this study's neighbours in a fixed, alphabetical-by-hash tour of them, not the closest in content. All 1,150 tagged studies.

• Porphyromonas gingivalis disrupts hippocampal circadian clock via PI3K/AKT pathway, exacerbating Alzheimer‐like pathology Alzheimer s & Dementia · 2026-06-01 · usefulness score 36/100 · Biomarkers
• Adenosine A2A receptors and brain injury: broad spectrum of neuroprotection, multifaceted actions and "fine tuning" modulation Progress in neurobiology · 2007-09-29 · usefulness score 36/100 · Vascular contributions
• Low-dose intranasal deferoxamine modulates memory, neuroinflammation, and the neuronal transcriptome in the streptozotocin rodent model of Alzheimer’s disease Frontiers in Neuroscience · 2025-01-13 · usefulness score 42/100 · Inflammation and the immune system

Studies sharing this one's topic tags

• Lymphoid gene expression supports neuroprotective microglia function Nature · 2025-11-05 · usefulness score 45/100 · shares: tdp-43, transgenic, mice
• Retraction: High-Affinity Naloxone Binding to Filamin A Prevents Mu Opioid Receptor-Gs Coupling / Retraction: Naloxone's Pentapeptide Binding Site on Filamin A Blocks Mu Opioid Receptor-Gs Coupling (among five Wang-authored papers retracted) PLOS ONE · 2022-03-30 · usefulness score 12/100 · shares: tdp-43, transgenic, mice
• Complement and microglia mediate early synapse loss in Alzheimer mouse models Science (New York, N.Y.) · 2016-03-31 · usefulness score 64/100 · shares: tdp-43, transgenic, mice
• Intranasal oxytocin for apathy in people with frontotemporal dementia (FOXY): a multicentre, randomised, double-blind, placebo-controlled, adaptive, crossover, phase 2a/2b superiority trial The Lancet Neurology · 2025 · usefulness score 69/100 · shares: tdp-43, transgenic, mice
• Clonal expansion of cytotoxic CD8⁺ T cells in lecanemab-associated ARIA Nature Communications · 2026-01-30 · usefulness score 53/100 · shares: tdp-43, transgenic, mice

Similar studies

• TDP-43 and FUS/TLS: emerging roles in RNA processing and neurodegeneration 2010 · Lewy body dementia
• RNA Binding Antagonizes Neurotoxic Phase Transitions of TDP-43 2019 · Lewy body dementia
• Physiological functions and pathobiology of TDP-43 and FUS/TLS proteins 2016 · Lewy body dementia
• TDP-43 regulates its mRNA levels through a negative feedback loop 2011 · Lewy body dementia
• Global analysis of TDP-43 interacting proteins reveals strong association with RNA splicing and translation machinery 2010 · Lewy body dementia
• A quantitative cell-based reporter links TDP-43 aggregation and dysfunction to define pathogenic mechanisms 2026 · Brain tissue and pathology

More on Brain tissue and pathology

• A review that covers this ground Understanding the role of TDP-43 and FUS/TLS in ALS and beyond Current opinion in neurobiology · 2011-08-02 · usefulness score 48/100
• Newest in this subject Inflammatory biomarker candidates in dementia with Lewy bodies: diagnostic classification, clinical associations, and survival Research Square · 2026-11-01 · Preprint — not yet peer-reviewed · usefulness score 16/100
• Newest in this subject TMEM106B C-Terminal fragment aggregation exacerbates α-synuclein and TDP-43 proteinopathy phenotypes bioRxiv · 2026-10-30 · Preprint — not yet peer-reviewed · usefulness score 16/100

See all studies in Brain tissue and pathology →