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DNA damage and defective DNA repair are extensively linked to neurodegeneration in Parkinson's disease (PD), but the underlying molecular mechanisms remain poorly understood. Here, we determined that the PD-associated protein DJ-1 plays an essential role in modulating DNA double-strand break (DSB) repair. Specifically, DJ-1 is a DNA damage response (DDR) protein that can be recruited to DNA damage sites, where it promotes DSB repair through both homologous recombination and nonhomologous end joining. Mechanistically, DJ-1 interacts directly with PARP1, a nuclear enzyme essential for genomic stability, and stimulates its enzymatic activity during DNA repair. Importantly, cells from PD patients with the DJ-1 mutation also have defective PARP1 activity and impaired repair of DSBs. In summary, our findings uncover a novel function of nuclear DJ-1 in DNA repair and genome stability maintenance, and suggest that defective DNA repair may contribute to the pathogenesis of PD linked to DJ-1 mutations. [ABSTRACT FROM AUTHOR]

DJ-1 mutations are rare causes of autosomal recessive early-onset Parkinson's disease (AR-EOPD) and relatively rarely reported in the Chinese population. Here, we used the whole-exome sequencing and Sanger sequencing to investigate DJ-1 mutations in the Chinese population and confirmed the pathogenicity of the mutation using primary fibroblasts established from skin biopsies. We identified a novel homozygous mutation (c.390delA, p.D131Tfs*3) in DJ-1 in a consanguineous Chinese family. The proband in this family had parkinsonism at the age of 22. His brain MRI indicated brain iron accumulation in the basal ganglia and cerebellum. The novel mutation caused DJ-1 protein deficiency, led to mitochondrial dysfunction, inhibited cell proliferation, and anti-oxidant defense. [ABSTRACT FROM AUTHOR]