title: Mammalian autophagy degrades nuclear constituents in response to tumorigenic stress.
abstract: During autophagy, double-membrane autophagosomes are observed in the cytoplasm. Thus, extensive studies have focused on autophagic turnover of cytoplasmic material. Whether autophagy has a role in degrading nuclear constituents is poorly understood. We reveal that the autophagy protein LC3/Atg8 directly interacts with the nuclear lamina protein LMNB1 (lamin B1), and binds to LMN/lamin-associated chromatin domains (LADs). Through these interactions, autophagy specifically mediates destruction of nuclear lamina during tumorigenic stress, such as by activated oncogenes and DNA damage. This nuclear lamina degradation upon aberrant cellular stress impairs cell proliferation by inducing cellular senescence, a stable form of cell-cycle arrest and a tumor-suppressive mechanism. Our findings thus suggest that, in response to cancer-promoting stress, autophagy degrades nuclear material to drive cellular senescence, as a means to restrain tumorigenesis. Our work provokes a new direction in studying the role of autophagy in the nucleus and in tumor suppression.
authors.affiliation: a Epigenetics Program, Department of Cell and Developmental Biology , Perelman School of Medicine , University of Pennsylvania , Philadelphia , PA , USA.
authors.forename: Zhixun
authors.initials: Z
authors.lastname: Dou
authors.affiliation: b Centre for Haemato-Oncology , Barts Cancer Institute, Queen Mary University of London , Charterhouse Square, London , UK.
authors.forename: Andrejs
authors.initials: A
authors.lastname: Ivanov
authors.affiliation: c Institute of Cancer Sciences , University of Glasgow and Beatson Institute for Cancer Research , Glasgow , UK.
authors.forename: Peter D
authors.initials: PD
authors.lastname: Adams
authors.affiliation: a Epigenetics Program, Department of Cell and Developmental Biology , Perelman School of Medicine , University of Pennsylvania , Philadelphia , PA , USA.
authors.forename: Shelley L
authors.initials: SL
authors.lastname: Berger
mesh_terms: D001343:Autophagy; D000071190:Autophagy-Related Protein 8 Family / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D016922:Cellular Senescence; D002843:Chromatin / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D003599:Cytoskeleton / Q000378:metabolism; D004249:DNA Damage; D015536:Down-Regulation; D044127:Epigenesis, Genetic; D006801:Humans; D034921:Lamin Type B / Q000378:metabolism*; D034882:Lamins / Q000378:metabolism; D009369:Neoplasms / Q000473:pathology*; D009685:Nuclear Envelope / Q000378:metabolism; D010588:Phagosomes / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D000071190:Autophagy-Related Protein 8 Family; D002843:Chromatin; C498698:GABARAPL2 protein, human; D034921:Lamin Type B; D034882:Lamins
keywords: Atg8; LADs; LC3; autophagy; lamin; nuclear lamina; nucleophagy; senescence; tumor suppression