SummaryAutophagy is an evolutionarily conserved catabolic pathway that has multiple roles in carcinogenesis and cancer therapy. It can inhibit the initiation of tumorigenesis through limiting cytoplasmic damage, genomic instability and inflammation, and the loss of certain autophagy genes can lead to cancer. Conversely, autophagy can also assist cells in dealing with stressful metabolic environments, thereby promoting cancer cell survival. In fact, some cancers rely on autophagy to survive and progress. Furthermore, tumour cells can exploit autophagy to cope with the cytotoxicity of certain anticancer drugs. By contrast, it appears that certain therapeutics require autophagy for the effective killing of cancer cells. Despite these dichotomies, it is clear that autophagy has an important, if complex, role in cancer. This is further exemplified by the fact that autophagy is connected with major cancer networks, including those driven by p53, mammalian target of rapamycin (mTOR), RAS and glutamine metabolism. In this Commentary, we highlight recent advances in our understanding of the role that autophagy has in cancer and discuss current strategies for targeting autophagy for therapeutic gain.This article is part of a Minifocus on Autophagy. For further reading, please see related articles: 'Ubiquitin-like proteins and autophagy at a glance' by Tomer Shpilka et al. (J. Cell Sci. 125, 2343-2348 and 'Autophagy and cell growth -the yin and yang of nutrient responses' by Thomas Neufeld (J. Cell Sci. 125, 2359-2368).

(Macro)autophagy delivers cellular constituents to lysosomes for degradation. Although a cytoplasmic process, autophagy-deficient cells accumulate genomic damage, but an explanation for this effect is currently unclear. We report here that inhibition of autophagy causes elevated proteasomal activity leading to enhanced degradation of checkpoint kinase 1 (Chk1), a pivotal factor for the errorfree DNA repair process, homologous recombination (HR). We show that loss of autophagy critically impairs HR and that autophagy-deficient cells accrue micronuclei and sub-G1 DNA, indicators of diminished genomic integrity. Moreover, due to impaired HR, autophagy-deficient cells are hyperdependent on nonhomologous end joining (NHEJ) for repair of DNA double-strand breaks. Consequently, inhibition of NHEJ following DNA damage in the absence of autophagy results in persistence of genomic lesions and rapid cell death. Because autophagy deficiency occurs in several diseases, these findings constitute an important link between autophagy and DNA repair and highlight a synthetic lethal strategy to kill autophagy-deficient cells.autophagy | DNA repair | cell death | synthetic lethality T he preservation of genome integrity is critical for the prevention of human disease. In addition, the maintenance of proteome integrity is also considered central to healthy cellular homeostasis. Macroautophagy, hereafter referred to as autophagy, is a process that is paramount in counteracting damage to cytoplasmic constituents (1). Upon initiation of autophagy, double-membraned vesicles termed "autophagosomes" form to encapsulate cargoes including damaged or misfolded proteins and organelles. These vesicles ultimately fuse with lysosomes and the acidic hydrolases provided by the lysosome degrade cargoes into constituent parts, which can be recycled into biosynthetic pathways or in some situations, further catabolized to produce energy for the cell (1). Autophagy functions at basal levels in virtually all cells and is a major mechanism for protein turnover and the only known mechanism for degradation of organelles (1). Due to its crucial role in maintaining cytoplasmic and therefore cellular homeostasis, perturbations in autophagy have been reported to be an important contributing factor in a spectrum of diseases, including Crohn's disease, lysosomal storage disorders, neurodegenerative diseases, and cancer (2-6).Autophagy operates in the cytoplasm and yet studies have shown that autophagy-deficient cells accumulate DNA damage (5). The reasons behind this observation, however, are not completely clear. Because the cellular environment of autophagy-deficient cells will cause accrual of damaged proteins with abnormal function and as a result accumulation of reactive oxygen species, it is easily conceivable that this will ultimately lead to a higher incidence of genetic lesions. However, even when autophagy is competent, our cells are already subject to an extremely high frequency of spontaneous DNA damage. The fact that this damage does not persist is ...