A recurrent chromosomal inversion suffices for driving escape from oncogene-induced senescence via subTAD reorganization.

Autor:	Zampetidis CP; Molecular Carcinogenesis Group, Department of Histology and Embryology, Faculty of Medicine, National Kapodistrian University of Athens, 11527 Athens, Greece., Galanos P; Genome Integrity Group, Danish Cancer Society Research Center, 2100 Copenhagen, Denmark. Electronic address: panos@cancer.dk., Angelopoulou A; Molecular Carcinogenesis Group, Department of Histology and Embryology, Faculty of Medicine, National Kapodistrian University of Athens, 11527 Athens, Greece., Zhu Y; Translational Epigenetics Group, Institute of Pathology, University Medical Center Göttingen, 37075 Göttingen, Germany., Polyzou A; Molecular Carcinogenesis Group, Department of Histology and Embryology, Faculty of Medicine, National Kapodistrian University of Athens, 11527 Athens, Greece., Karamitros T; Unit of Bioinformatics and Applied Genomics, Department of Microbiology, Hellenic Pasteur Institute, 11521 Athens, Greece., Kotsinas A; Molecular Carcinogenesis Group, Department of Histology and Embryology, Faculty of Medicine, National Kapodistrian University of Athens, 11527 Athens, Greece., Lagopati N; Molecular Carcinogenesis Group, Department of Histology and Embryology, Faculty of Medicine, National Kapodistrian University of Athens, 11527 Athens, Greece., Mourkioti I; Molecular Carcinogenesis Group, Department of Histology and Embryology, Faculty of Medicine, National Kapodistrian University of Athens, 11527 Athens, Greece., Mirzazadeh R; Science for Life Laboratory, Division of Genome Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institute, 171 77 Solna, Stockholm, Sweden., Polyzos A; Sanford I. Weill Department of Medicine, Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10065, USA., Garnerone S; Science for Life Laboratory, Division of Genome Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institute, 171 77 Solna, Stockholm, Sweden., Mizi A; Translational Epigenetics Group, Institute of Pathology, University Medical Center Göttingen, 37075 Göttingen, Germany., Gusmao EG; Translational Epigenetics Group, Institute of Pathology, University Medical Center Göttingen, 37075 Göttingen, Germany., Sofiadis K; Translational Epigenetics Group, Institute of Pathology, University Medical Center Göttingen, 37075 Göttingen, Germany., Gál Z; Nucleolar Stress and Disease Group, Danish Cancer Society Research Center, 2100 Copenhagen, Denmark., Larsen DH; Nucleolar Stress and Disease Group, Danish Cancer Society Research Center, 2100 Copenhagen, Denmark., Pefani DE; Laboratories of Biology, Medical School, University of Patras, 26504 Rio, Greece., Demaria M; University of Groningen (RUG), European Research Institute for the Biology of Aging (ERIBA), University Medical Center Groningen (UMCG), 9713 AV Groningen, the Netherlands., Tsirigos A; Department of Pathology, NYU School of Medicine, New York, NY 10016, USA., Crosetto N; Science for Life Laboratory, Division of Genome Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institute, 171 77 Solna, Stockholm, Sweden., Maya-Mendoza A; DNA Replication and Cancer Group, Danish Cancer Society Research Center, 2100 Copenhagen, Denmark., Papaspyropoulos A; Molecular Carcinogenesis Group, Department of Histology and Embryology, Faculty of Medicine, National Kapodistrian University of Athens, 11527 Athens, Greece., Evangelou K; Molecular Carcinogenesis Group, Department of Histology and Embryology, Faculty of Medicine, National Kapodistrian University of Athens, 11527 Athens, Greece., Bartek J; Genome Integrity Group, Danish Cancer Society Research Center, 2100 Copenhagen, Denmark; Science for Life Laboratory, Division of Genome Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institute, 171 77 Solna, Stockholm, Sweden. Electronic address: jb@cancer.dk., Papantonis A; Translational Epigenetics Group, Institute of Pathology, University Medical Center Göttingen, 37075 Göttingen, Germany; Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931 Cologne, Germany. Electronic address: argyris.papantonis@med.uni-goettingen.de., Gorgoulis VG; Molecular Carcinogenesis Group, Department of Histology and Embryology, Faculty of Medicine, National Kapodistrian University of Athens, 11527 Athens, Greece; Biomedical Research Foundation, Academy of Athens, 11527 Athens, Greece; Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine & Health, University of Manchester, M20 4GJ Manchester, UK; Center for New Biotechnologies and Precision Medicine, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; Faculty of Health and Medical Sciences, University of Surrey, Surrey GU2 7YH, UK. Electronic address: vgorg@med.uoa.gr.
Jazyk:	angličtina
Zdroj:	Molecular cell [Mol Cell] 2021 Dec 02; Vol. 81 (23), pp. 4907-4923.e8. Date of Electronic Publication: 2021 Nov 17.
DOI:	10.1016/j.molcel.2021.10.017
Abstrakt:	Oncogene-induced senescence (OIS) is an inherent and important tumor suppressor mechanism. However, if not removed timely via immune surveillance, senescent cells also have detrimental effects. Although this has mostly been attributed to the senescence-associated secretory phenotype (SASP) of these cells, we recently proposed that "escape" from the senescent state is another unfavorable outcome. The mechanism underlying this phenomenon remains elusive. Here, we exploit genomic and functional data from a prototypical human epithelial cell model carrying an inducible CDC6 oncogene to identify an early-acquired recurrent chromosomal inversion that harbors a locus encoding the circadian transcription factor BHLHE40. This inversion alone suffices for BHLHE40 activation upon CDC6 induction and driving cell cycle re-entry of senescent cells, and malignant transformation. Ectopic overexpression of BHLHE40 prevented induction of CDC6-triggered senescence. We provide strong evidence in support of replication stress-induced genomic instability being a causative factor underlying "escape" from oncogene-induced senescence. Competing Interests: Declaration of interests The authors declare no competing interests. (Copyright © 2021 Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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