Autophagy Protects Integrity of Tumor Suppressors From Replication Stress

Abstract

Several studies support the role of autophagy in maintenance of genome integrity and cancer suppression. However, it remains unclear how autophagy deficiency contributes to mutagenic or epigenetic alterations during the early stages of carcinogenesis. In this study, we show that compromised autophagy led to deregulated activity of Fanconi anemia tumor suppressor pathway, which plays a major role in the suppression of genomic alterations caused by replication stress. We found that expression of FA protein FANCF is significantly reduced in autophagy-deficient cells in a manner that epigenetic alteration drives the defect. Comprehensive genome-wide analysis revealed that autophagy deficiency causes copy number variations at common fragile sites and multiple other loci encoding tumor suppressors, leading to their deregulation. Our results suggest that autophagy deficiency drives genetic and epigenetic catastrophe escalated by the defect in FA-pathway, disrupts proper control of other tumor suppressors and promotes tumorigenesis at the early stage.