BIRC5/Survivin is a member of the inhibitor-of-apoptosis proteins (IAPs) family. It is long known that overexpression of BIRC5 promotes tumorigenesis, tumor drug resistance, and metastasis. Similar to the other IAPs family members, BIRC5 exhibits both the direct and indirect caspase and apoptosis inhibition activities in cells. Recently, we discovered that BIRC5 negatively-modulates autophagy in part through inhibition of the formation of autophagosome, via interference with the complex formation of ATG12-ATG5-ATG16L. Surprisingly, despite the consensus in the field that autophagy upregulation positively-regulates the process of DNA repair and the maintenance of genomic stability, we found that downregulation of BIRC5 upregulates autophagy and promotes autophagy-mediated DNA damage and DNA leakage in human cancer and mouse embryonic fibroblast cells, suggesting that excessive autophagy, at least at certain levels and under certain circumstances, could promote genomic instability in cells.
