The “Dark Side” of autophagy on the maintenance of genome stability: Does it really exist during excessive activation?

Dysregulation of DNA damage response/repair and genomic instability promote tumorigenesis and the development of various neurological diseases. Autophagy is a dynamic catabolic process used for removing unnecessary or dysfunctional proteins and organelles in cells. Despite the consensus in the field that upregulation of autophagy promotes the initiation of the DNA damage response and assists the process of homologous recombination upon genotoxic stress, a few studies showed that upregulation of autophagy (or excessive autophagy), under certain circumstances, triggers caspase/apoptosis-independent DNA damage and promotes genomic instability in cells. As the cytoprotective and the DNA repairing roles of autophagy have been discussed extensively in different reviews, here, we mainly focus on describing the latest studies which reported the “opposite” roles of autophagy (or excessive autophagy). We will discuss whether the “dark side” (i.e., the opposite/unconventional effect) of autophagy on the maintenance of DNA integrity and genomic stability really does exist in cells and if it does, will it be one of the yet-to-be-identified causes of cancer, in this review.