TDP-43 dysfunction results in R-loop accumulation and DNA replication defects.

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• TAR DNA-binding protein 43 (TDP-43) aggregation is linked to neurodegenerative diseases like ALS and FTD.
• TDP-43 loss is known to increase DNA damage and reduce cell viability.
• The precise role of TDP-43 in maintaining genome stability was previously unclear.

Purpose of the Study:

• To investigate the function of TDP-43 in preventing genome instability.
• To elucidate the mechanism by which TDP-43 loss leads to DNA damage.
• To explore the link between TDP-43 proteinopathies and genomic instability.

Main Methods:

• Analysis of R-loop formation in cells with and without TDP-43.
• Assessment of DNA replication stress upon TDP-43 loss.
• Investigation of TDP-43's nucleic acid-binding and self-assembly activities.
• Examination of TDP-43 function in neuronal cells.

Main Results:

• Loss of TDP-43 significantly increases R-loop formation in a transcription-dependent manner.
• TDP-43 depletion leads to DNA replication stress and genomic instability.
• TDP-43's nucleic acid-binding and self-assembly are critical for inhibiting R-loops and maintaining replication.
• Cytoplasmic aggregation of TDP-43 impairs its R-loop regulatory function.
• Neurons lacking TDP-43 exhibit increased R-loop accumulation and DNA damage.

Conclusions:

• TDP-43 plays a crucial role in maintaining genomic stability via a co-transcriptional process.
• Preventing aberrant R-loop accumulation is a key function of TDP-43.
• TDP-43 dysfunction and aggregation contribute to the pathogenesis of TDP-43 proteinopathies through genomic instability.