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

Authors

Vincent E Provasek
Albino Bacolla
Suganya Rangaswamy
Manohar Kodavati
Joy Mitra
Issa O Yusuf
Vikas H Malojirao
Velmarini Vasquez
Gavin W Britz
Guo-Min Li
Zuoshang Xu
Sankar Mitra
Ralph M Garruto
John A Tainer
Muralidhar L Hegde

Publication Date

9-23-2025

Journal

Nucleic Acids Research

DOI

10.1093/nar/gkaf920

PMID

40985771

PMCID

PMC12455596

PubMedCentral® Posted Date

9-23-2025

PubMedCentral® Full Text Version

Post-print

Abstract

TDP43 is an RNA/DNA-binding protein increasingly recognized for its role in neurodegenerative conditions, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). As characterized by its aberrant nuclear export and cytoplasmic aggregation, TDP43 proteinopathy is a hallmark feature in over 95% of ALS/FTD cases, leading to detrimental cytosolic aggregates and a reduction in nuclear functionality in neurons. Building on our prior work linking TDP43 proteinopathy to the accumulation of DNA double-strand breaks (DSBs) in neurons, the present investigation uncovers a novel regulatory relationship between TDP43 and DNA mismatch repair (MMR) gene expression. Here, we show that TDP43 depletion or overexpression directly affects the expression of key MMR genes. Alterations include changes in MLH1, MSH2, MSH3, MSH6, and PMS2 levels across various primary cell lines, independent of their proliferative status. Our results specifically establish that TDP43 selectively influences the expression of MLH1 and MSH6 by influencing their alternative transcript splicing patterns and stability. We furthermore find that aberrant MMR gene expression is linked to TDP43 proteinopathy in two distinct ALS mouse models and in post-mortem brain and spinal cord tissues of ALS patients. Notably, MMR depletion resulted in the partial rescue of TDP43 proteinopathy-induced DNA damage and signaling. Moreover, bioinformatics analysis of the TCGA cancer database reveals significant associations between TDP43 expression, MMR gene expression, and mutational burden across multiple cancers. Collectively, our findings implicate TDP43 as a critical regulator of the MMR pathway and unveil its broad impact on the etiology of both neurodegenerative and neoplastic pathologies.

Keywords

DNA-Binding Proteins, Humans, Animals, DNA Mismatch Repair, Mice, Genomic Instability, MutL Protein Homolog 1, Amyotrophic Lateral Sclerosis, MutS Homolog 3 Protein, MutS Homolog 2 Protein, Mismatch Repair Endonuclease PMS2, Neurons, DNA Breaks, Double-Stranded, Gene Expression Regulation

Published Open-Access

yes

Recommended Citation

Provasek, Vincent E; Bacolla, Albino; Rangaswamy, Suganya; et al., "RNA/DNA-Binding Protein TDP43 Regulates DNA Mismatch Repair Genes With Implications for Genome Stability" (2025). Faculty, Staff and Student Publications. 5060.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/5060