Defects in DNA repair pathways can lead to genomic instability in multiple tumor types, which contributes to tumor immunogenicity. Inhibition of DNA damage response (DDR) has been reported to increase tumor susceptibility to anticancer immunotherapy. However, the interplay between DDR and the immune signaling pathways remains unclear. In this review, we will discuss how a deficiency in DDR affects anti-tumor immunity, highlighting the cGAS-STING axis as an important link. We will also review the clinical trials that combine DDR inhibition and immune-oncology treatments. A better understanding of these pathways will help exploit cancer immunotherapy and DDR pathways to improve treatment outcomes for various cancers.
Mitophagy is essential for the maintenance of mitochondrial quality control (MQC) and neuronal survival. Defects in mitophagy have been implicated in the onset and progression of Parkinson’s disease (PD). However, the underlying mechanisms of mitophagy in the pathogenesis of PD remains unclear. Here, the AAA+ ATPase Thorase was identified being essential for mitophagy. Mice lacking Thorase exhibited PD-like behavior and α-synucleinopathy in the brains. Genetic deletion of Thorase exacerbated phenotypes of α-synucleinopathy in a familial PD-like A53T mouse model, whereas overexpression of Thorase prevented α-syn accumulation in vivo. Thorase regulates the balance of mitochondrial fusion/fission.Thorase deficiency resulted in more fragmented mitochondria and the blockage of dysfunctional mitochondrion degradation through PINK1/Parkin-mediated mitophagy. Thorase directly interacted with α-syn and regulated ubiquitinated α-syn degradation through mitophagy. The discoveries in this study place Thorase as a novel druggable target for pharmaceutical intervention of PD.
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