Abstract
ABSTRACTMacroautophagy (hereafter autophagy) is a cellular catabolic process that is essential for maintaining tissue homeostasis and regulating various normal and pathologic processes in human diseases including cancer. One cancer-driving process is accumulation of genetic mutations due to impaired DNA damage repair, including nucleotide excision repair. Here we show that autophagy positively regulates nucleotide excision repair through enhancing DNA damage recognition by the DNA damage sensor proteins XPC and DDB2 via 2 pathways. First, autophagy deficiency downregulates the transcription of XPC through TWIST1-dependent activation of the transcription repressor complex E2F4-RBL2. Second, autophagy deficiency impairs the recruitment of DDB2 to ultraviolet radiation (UV)-induced DNA damage sites through TWIST1-mediated inhibition of EP300. In mice, the pharmacological autophagy inhibitor Spautin-1 promotes UVB-induced tumorigenesis, whereas the autophagy inducer rapamycin reduces UVB-induced tumorigenesis. These findings demonstrate the crucial role of autophagy in maintaining proper nucleotide excision repair in mammalian cells and suggest a previously unrecognized tumor-suppressive mechanism of autophagy in cancer.
Highlights
nucleotide excision repair (NER) is a versatile DNA repair pathway that eliminates a wide variety of helix-distorting base lesions induced by environmental carcinogenic sources, including 2 products induced by solar UV B radiation (UVB) radiation, namely, cyclobutane pyrimidine dimers (CPD) and (6-4) photoproducts (6-4PP), as well as other bulky adducts induced by air pollutants.[21,22,23,24,25,26,27]
To determine whether autophagy plays a role in NER, we compared NER capacity in mouse embryonic fibroblast (MEF) cells from wild-type (WT) mice with that from mice that were autophagy-deficient through loss of various autophagy-related (Atg) genes
In HaCaT cells ATG7 knockdown inhibited autophagy and decreased the basal XPC protein level and UVB-induced XPC ubiquitination (Fig. 1G), a biochemical process critical for DNA damage recognition mediated by the ultraviolet radiation (UV)-DDB complex.[40,41,42]
Summary
Occurring at a low basal level, macroautophagy (hereafter autophagy) can be induced to maintain tissue homeostasis in response to a variety of physiological and pathological stresses,[1] including solar UV B radiation (UVB).[2,3] Autophagy dysfunction is associated with multiple human diseases, such as neurodegeneration, infectious diseases, metabolic diseases, cardiovascular diseases, aging, and cancer.[4,5,6,7]In carcinogenesis and cancer progression, autophagy can be both oncogenic and tumor suppressive.[6,7,8,9] On the one hand, autophagy promotes tumorigenesis and tumor progression at least in part through promoting cell survival and invasion.[1,2,3,10,11] On the other hand, autophagy suppresses tumorigenesis and tumor progression through selectively degrading SQSTM1/p62, an autophagy receptor protein and signaling adaptor that promotes inflammation, cell proliferation and migration,[12,13,14,15,16] through removing damaged proteins and organelles to prevent genomic damage,[4,6,15,17,18] or by promoting homologous recombination DNA repair in response to ionizing radiation-induced DNA double-strand breaks in mammalian cells.[19,20]In addition, autophagy may suppress tumor initiation by regulating another essential DNA repair pathway: nucleotide excision repair (NER). Occurring at a low basal level, macroautophagy (hereafter autophagy) can be induced to maintain tissue homeostasis in response to a variety of physiological and pathological stresses,[1] including solar UV B radiation (UVB).[2,3] Autophagy dysfunction is associated with multiple human diseases, such as neurodegeneration, infectious diseases, metabolic diseases, cardiovascular diseases, aging, and cancer.[4,5,6,7]. NER is a versatile DNA repair pathway that eliminates a wide variety of helix-distorting base lesions induced by environmental carcinogenic sources, including 2 products induced by solar UVB radiation, namely, cyclobutane pyrimidine dimers (CPD) and (6-4) photoproducts (6-4PP), as well as other bulky adducts induced by air pollutants.[21,22,23,24,25,26,27] Defects in the global genome NER (GG-NER) subpathway cause xeroderma pigmentosum (XP), an autosomal recessive disorder predisposing affected individuals to cancer development in the skin, and in the brain and lungs.[24,25,28,29] Seven XP group genes plus one variant have been identified as indispensable NER factors,[24,25,29,30,31] among which XPC and DDB2 are essential for GG-NER-specific damage recognition.[32,33,34]
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