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

Area of Science:

• Molecular Biology
• Neuroscience
• Genetics

Background:

• TDP-43 and FUS are RNA-binding proteins linked to neurodegenerative diseases.
• Dysfunctional RNA processing is implicated in diseases like ALS and FTD.
• R-loops are implicated in genome instability and disease.

Purpose of the Study:

• To investigate the role of TDP-43 and FUS in transcription termination.
• To elucidate the involvement of the R1810me2s-SMN pathway in TDP-43 and FUS function.
• To establish a mechanistic link between TDP-43/FUS, R-loop resolution, and neurodegeneration.

Main Methods:

• Chromatin recruitment assays to study TDP-43 and FUS.
• RNAPII termination assays to assess termination efficiency.
• Transcriptome-wide analyses to identify TDP-43 binding sites and R-loop formation.
• Assays to evaluate the impact of RNA-binding activity on TDP-43 function.

Main Results:

• TDP-43 and FUS are recruited to chromatin via the R1810me2s-SMN pathway, promoting transcription termination.
• Disruption of this pathway leads to defective RNAPII termination, R-loop accumulation, and DNA damage.
• TDP-43 RNA-binding is crucial for its role in R-loop resolution and transcription termination.
• TDP-43 binding sites correlate with R-loop formation regions.

Conclusions:

• TDP-43 and FUS play critical roles in transcription termination through the R1810me2s-SMN pathway.
• Impaired R-loop resolution by TDP-43/FUS contributes to genome instability.
• These findings offer insights into the pathogenesis of ALS and FTD.