Nuclear DJ-1 Regulates DNA Damage Repair via the Regulation of PARP1 Activity

Abstract

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.

Advancements in Genetic and Biochemical Insights: Unraveling the Etiopathogenesis of Neurodegeneration in Parkinson’s Disease

“…Along with PARP1, DJ-1 preserves genomic stability, and disruption of this connection might have an influence on DNA damage accumulation, impaired DNA repair, and, ultimately, neurodegeneration. Therefore, faulty DNA repair is associated with the PD pathophysiology brought on by DJ-1 mutations [207].…”

“…Along with PARP1, DJ-1 preserves genomic stability, and disruption of this connection might have an influence on DNA damage accumulation, impaired DNA repair, and, ultimately, neurodegeneration. Therefore, faulty DNA repair is associated with the PD pathophysiology brought on by DJ-1 mutations [207]. The antioxidant capabilities, antiapoptotic implications, and impact on mitochondrial respiration, shape, shifts, and biosynthesis are a brief overview of the neuroprotective actions exerted by DJ-1 [209].…”