RNA/DNA Binding Protein TDP43 Regulates DNA Mismatch Repair Genes with Implications for Genome Stability

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• TAR DNA-binding protein 43 (TDP43) pathology is linked to neurodegenerative diseases like ALS and FTD.
• TDP43 dysfunction causes genomic instability in neurons.
• Prior research connected TDP43 to DNA double-strand breaks (DSBs).

Purpose of the Study:

• To investigate the novel role of TDP43 in the DNA mismatch repair (MMR) pathway.
• To elucidate how TDP43 influences MMR gene expression and function.
• To explore the implications of TDP43-MMR interaction in neurodegeneration and cancer.

Main Methods:

• TDP43 depletion and overexpression experiments in neuronal models.
• Analysis of key MMR gene expression (MLH1, MSH6, MSH2, MSH3, PMS2).
• Validation in ALS mouse models, patient-derived cells, and brain tissues.
• Bioinformatics analysis of TCGA cancer database.

Main Results:

• TDP43 modulates MLH1 and MSH6 expression via alternative splicing and transcript stability.
• MMR pathway disruption partially rescues TDP43-induced DNA damage.
• Significant correlations found between TDP43, MMR genes, and mutational burden in cancers.

Conclusions:

• TDP43 is identified as a critical regulator of the DNA mismatch repair pathway.
• TDP43's role in MMR contributes to genomic instability in neurodegenerative diseases.
• Findings suggest TDP43-MMR interplay is relevant to both neurological disorders and cancer.