FUS Unveiled in Mitochondrial DNA Repair and Targeted Ligase-1 Expression Rescues Repair-Defects in FUS-Linked
Manohar Kodavati1, Haibo Wang1, Wenting Guo2,3
1Division of DNA Repair Research within the Center for Neuroregeneration, Department of Neurosurgery, Houston Methodist Research Institute, Houston, TX 77030, USA.
Abstract:
This study establishes the physiological role of Fused in Sarcoma (FUS) in mitochondrial DNA (mtDNA) repair and highlights its implications to the pathogenesis of FUS-associated neurodegenerative diseases such as Amyotrophic lateral sclerosis (ALS). Endogenous FUS interacts with and recruits mtDNA Ligase IIIα (mtLig3) to DNA damage sites within mitochondria, a relationship essential for maintaining mtDNA repair and integrity in healthy cells. Using ALS patient-derived FUS mutant cell lines, a transgenic mouse model, and human autopsy samples, we discovered that compromised FUS functionality hinders mtLig3's repair role, resulting in increased mtDNA damage and mutations. These alterations cause various manifestations of mitochondrial dysfunction, particularly under stress conditions relevant to disease pathology. Importantly, rectifying FUS mutations in patient-derived induced pluripotent cells (iPSCs) preserves mtDNA integrity. Similarly, targeted introduction of human DNA Ligase 1 restores repair mechanisms and mitochondrial activity in FUS mutant cells, suggesting a potential therapeutic approach. Our findings unveil FUS's critical role in mitochondrial health and mtDNA repair, offering valuable insights into the mechanisms underlying mitochondrial dysfunction in FUS-associated neurodegeneration.
Insights
Fused in Sarcoma (FUS) protein is vital for mitochondrial DNA (mtDNA) repair. Impaired FUS function in neurodegenerative diseases like ALS leads to mtDNA damage and mitochondrial dysfunction.
Area of Science:
- Molecular Biology
- Neuroscience
- Genetics
Background:
- The protein Fused in Sarcoma (FUS) plays a crucial role in cellular processes.
- Dysfunction of FUS is implicated in neurodegenerative diseases, including Amyotrophic Lateral Sclerosis (ALS).
- Mitochondrial DNA (mtDNA) integrity is essential for cellular health and function.
Approach:
- Investigated the interaction between FUS and mitochondrial DNA Ligase IIIα (mtLig3) in DNA repair.
- Utilized ALS patient-derived cell lines, a transgenic mouse model, and human autopsy samples to study FUS mutations.
- Assessed the impact of FUS dysfunction on mtDNA repair, mutations, and mitochondrial function under stress conditions.
Key Points:
- Endogenous FUS recruits mtLig3 to mitochondrial DNA damage sites, crucial for repair.
- FUS mutations impair mtLig3's function, leading to increased mtDNA damage and mutations.
- Mitochondrial dysfunction, particularly under stress, is a consequence of compromised FUS activity.
- Correcting FUS mutations in patient-derived cells restores mtDNA integrity.
- Restoring DNA repair mechanisms, e.g., via DNA Ligase 1, improves mitochondrial function in FUS mutant cells.
Conclusions:
- Fused in Sarcoma (FUS) is physiologically essential for mitochondrial DNA repair.
- Compromised FUS function contributes to mitochondrial dysfunction in FUS-associated neurodegenerative diseases.
- Targeting FUS-mediated repair pathways may offer therapeutic strategies for ALS and related disorders.
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