Molecular Basis of DNA Repair Defects in FUS-Associated ALS: Implications of a New Paradigm and Its Potential as Therapeutic Target
Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron disorder, characterized by a diverse etiopathology. While ALS is predominantly sporadic, mutations in one or more of a dozen risk factors have been linked to approximately 10% of familial ALS patients. The multifunctional RNA/DNA-bind...
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| Main Authors: | , |
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| Format: | Ebooks |
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IntechOpen,
2020-06-18.
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| Summary: | Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron disorder, characterized by a diverse etiopathology. While ALS is predominantly sporadic, mutations in one or more of a dozen risk factors have been linked to approximately 10% of familial ALS patients. The multifunctional RNA/DNA-binding protein fused in sarcoma (FUS) is one such protein whose autosomal dominant missense mutations were identified in a subset of familial and sporadic ALS patients. Initial studies linked FUS with both RNA-related and genome maintenance functions, yet the mechanisms and potential implications to neurodegeneration were not completely understood. We recently identified a novel function of FUS in repairing single-strand break (SSB) in the genome. FUS directly interacts and recruits XRCC1/DNA Ligase IIIα (LigIII) to DNA oxidative damage sites in a PARP1 activity-dependent manner, which facilitates optimal oxidative genome damage repair. Besides, FUS regulates DNA strand break sealing by enhancing ligation activity of LigIII. The mutation of FUS induces accumulation of oxidative DNA damage as well as DNA repair deficiency in ALS patients. The novel findings provide insights into a previously undescribed mechanism of DNA repair defect in FUS-associated neurodegeneration, and raise the pentientials of developing neuroprotective therapies by targeting DNA break ligating defects. |
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| Item Description: | https://mts.intechopen.com/articles/show/title/molecular-basis-of-dna-repair-defects-in-fus-associated-als-implications-of-a-new-paradigm-and-its-p |