title: Loss of p53-mediated cell-cycle arrest, senescence and apoptosis promotes genomic instability and premature aging.
abstract: Although p53-mediated cell cycle arrest, senescence and apoptosis are well accepted as major tumor suppression mechanisms, the loss of these functions does not directly lead to tumorigenesis, suggesting that the precise roles of these canonical activities of p53 need to be redefined. Here, we report that the cells derived from the mutant mice expressing p533KR, an acetylation-defective mutant that fails to induce cell-cycle arrest, senescence and apoptosis, exhibit high levels of aneuploidy upon DNA damage. Moreover, the embryonic lethality caused by the deficiency of XRCC4, a key DNA double strand break repair factor, can be fully rescued in the p533KR/3KR background. Notably, despite high levels of genomic instability, p533KR/3KRXRCC4-/- mice, unlike p53-/- XRCC4-/- mice, are not succumbed to pro-B-cell lymphomas. Nevertheless, p533KR/3KR XRCC4-/- mice display aging-like phenotypes including testicular atrophy, kyphosis, and premature death. Further analyses demonstrate that SLC7A11 is downregulated and that p53-mediated ferroptosis is significantly induced in spleens and testis of p533KR/3KRXRCC4-/- mice. These results demonstrate that the direct role of p53-mediated cell cycle arrest, senescence and apoptosis is to control genomic stability in vivo. Our study not only validates the importance of ferroptosis in p53-mediated tumor suppression in vivo but also reveals that the combination of genomic instability and activation of ferroptosis may promote aging-associated phenotypes.
authors.affiliation: Institute for Cancer Genetics, and Department of Pathology and Cell Biology, College of Physicians and Surgeons, Columbia University, New York, NY, USA.|Herbert Irving Comprehensive Cancer Center, College of Physicians and Surgeons, Columbia University, New York, NY, USA.
authors.forename: Tongyuan
authors.initials: T
authors.lastname: Li
authors.affiliation: Institute for Cancer Genetics, and Department of Pathology and Cell Biology, College of Physicians and Surgeons, Columbia University, New York, NY, USA.|Herbert Irving Comprehensive Cancer Center, College of Physicians and Surgeons, Columbia University, New York, NY, USA.
authors.forename: Xiangyu
authors.initials: X
authors.lastname: Liu
authors.affiliation: Institute for Cancer Genetics, and Department of Pathology and Cell Biology, College of Physicians and Surgeons, Columbia University, New York, NY, USA.|Herbert Irving Comprehensive Cancer Center, College of Physicians and Surgeons, Columbia University, New York, NY, USA.
authors.forename: Le
authors.initials: L
authors.lastname: Jiang
authors.affiliation: Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: James
authors.initials: J
authors.lastname: Manfredi
authors.affiliation: Institute for Cancer Genetics, and Department of Pathology and Cell Biology, College of Physicians and Surgeons, Columbia University, New York, NY, USA.|Herbert Irving Comprehensive Cancer Center, College of Physicians and Surgeons, Columbia University, New York, NY, USA.|Department of Pediatrics, College of Physicians and Surgeons, Columbia University, New York, NY, USA.
authors.forename: Shan
authors.initials: S
authors.lastname: Zha
authors.affiliation: Institute for Cancer Genetics, and Department of Pathology and Cell Biology, College of Physicians and Surgeons, Columbia University, New York, NY, USA.|Herbert Irving Comprehensive Cancer Center, College of Physicians and Surgeons, Columbia University, New York, NY, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Gu
mesh_terms: D019588:Aging, Premature / Q000503:physiopathology*; D000818:Animals; D017209:Apoptosis; D059447:Cell Cycle Checkpoints; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D004249:DNA Damage; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000502:physiology; D042822:Genomic Instability; D016393:Lymphoma, B-Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
chemical_list: D004268:DNA-Binding Proteins; D016159:Tumor Suppressor Protein p53; C511788:XRCC4 protein, mouse
keywords: acetylation; ferroptosis; genomic instability; p53; tumor suppression