期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2015
卷号：112
期号：3
页码：773-778
DOI：10.1073/pnas.1409563112
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceIt is known that autophagy plays a major role in cellular homeostasis and impaired autophagy has been implicated in various forms of human disease. Here we investigate one way in which autophagy is critically connected to cellular integrity by showing that autophagy loss diminishes DNA repair by the error-free process, homologous recombination. As a result, this causes reliance on the error-prone process of nonhomologous end joining for repair of DNA double-strand breaks, providing one explanation of why autophagy-deficient cells accumulate genomic damage. These findings therefore have important implications for diseases in which autophagy is impaired and for therapeutic strategies designed to inhibit autophagy, particularly if autophagy inhibition is undertaken in combination with agents that cause genomic damage. (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 error-free 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.
关键词：autophagy ; DNA repair ; cell death ; synthetic lethality
