TDP43 Interacts with MLH1 and MSH6 Proteins in A DNA Damage-Inducible Manner.

Autor:	Provasek VE; Division of DNA Repair Research within the Center for Neuroregeneration, Department of Neurosurgery, Houston Methodist Research Institute, Houston, TX 77030, USA.; School of Medicine, Texas A&M University, College Station, TX 77843, USA., Kodavati M; Division of DNA Repair Research within the Center for Neuroregeneration, Department of Neurosurgery, Houston Methodist Research Institute, Houston, TX 77030, USA., Kim B; Department of Neuroscience, Rice University, Houston, TX 77006., Mitra J; Division of DNA Repair Research within the Center for Neuroregeneration, Department of Neurosurgery, Houston Methodist Research Institute, Houston, TX 77030, USA., Hegde ML; Division of DNA Repair Research within the Center for Neuroregeneration, Department of Neurosurgery, Houston Methodist Research Institute, Houston, TX 77030, USA.; School of Medicine, Texas A&M University, College Station, TX 77843, USA.; Department of Neuroscience, Weill Cornell Medical College, New York, NY 10065, USA.
Jazyk:	angličtina
Zdroj:	Research square [Res Sq] 2024 May 21. Date of Electronic Publication: 2024 May 21.
DOI:	10.21203/rs.3.rs-4439430/v1
Abstrakt:	Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that affects the motor neuron. One aspect of the neuropathology involved in ALS includes increased genomic damage and impaired DNA repair capability. The TAR-DNA binding protein 43 (TDP43) has been associated with both sporadic and familial forms of ALS, and is typically observed as cytosolic mislocalization of protein aggregates, termed TDP43 proteinopathy. TDP43 is a ubiquitous RNA/DNA binding protein with functional implications in a wide range of disease processes, including the repair of DNA double strand breaks (DSBs). While TDP43 is widely known to regulate RNA metabolism, our lab has reported it also functions directly at the protein level to facilitate DNA repair. Here, we show that TDP43 protein interacts with DNA mismatch repair (MMR) proteins MLH1 and MSH6 in a DNA damage-inducible manner. We utilized differentiated SH-SY5Y neuronal cultures to identify this inducible relationship using complimentary approaches of proximity ligation assay (PLA) and co-immunoprecipitation (CoIP) assay. We observed that signals of TDP43 interaction with MLH1 and MSH6 increased significantly following a 2 hr treatment of 10μM methylmethanesulfonate (MMS), a DNA alkylating agent used to induce MMR repair. Likewise, we observed this effect was abolished in cell lines treated with siRNA directed against TDP43. Finally, we demonstrated these protein interactions were significantly increased in lumbar spinal cord samples of ALS-affected patients compared to age-matched controls. These results will inform our future studies to understand the mechanisms and consequences of this TDP43-MMR interaction in the context of ALS affected neurons. Competing Interests: Conflicts of Interest The authors declare no conflicts of interest.
Databáze:	MEDLINE
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