Nuclear-receptor-mediated telomere insertion leads to genome instability in ALT cancers.
The breakage-fusion-bridge cycle is a classical mechanism of telomere-driven genome instability in which dysfunctional telomeres are fused to other chromosomal extremities, creating dicentric chromosomes that eventually break at mitosis. Here, we uncover a distinct pathway of telomere-driven genome instability, specifically occurring in cells that maintain telomeres with the alternative lengthening of telomeres mechanism. We show that, in these cells, telomeric DNA is added to multiple discrete sites throughout the genome, corresponding to regions regulated by NR2C/F transcription factors. These proteins drive local telomere DNA addition by recruiting telomeric chromatin. This mechanism, which we name targeted telomere insertion (TTI), generates potential common fragile sites that destabilize the genome. We propose that TTI driven by NR2C/F proteins contributes to the formation of complex karyotypes in ALT tumors.
INSERM AVENIR Team, Institute of Human Genetics, CNRS UPR 1142, 141 rue de la Cardonille, 34396 Montpellier, France.
Paulina
P
Marzec
INSERM AVENIR Team, Institute of Human Genetics, CNRS UPR 1142, 141 rue de la Cardonille, 34396 Montpellier, France.
Claudia
C
Armenise
Translational Research, Department of Biopathology, Institut Bergonié, 229 cours de l'Argonne, 33076 Bordeaux, France; INSERM U916, 229 cours de l'Argonne, 33076 Bordeaux, France.
Gaëlle
G
Pérot
Laboratory of Genetics and Gene Therapy, Center of Basic Research II, Biomedical Research Foundation of the Academy of Athens, 11527 Athens, Greece.
Fani-Marlen
FM
Roumelioti
Institut de Génétique Moléculaire de Montpellier, CNRS-UMR5535, 1919 route de Mende, 34293 Montpellier Cedex 5, France.
Eugenia
E
Basyuk
Laboratory of Genetics and Gene Therapy, Center of Basic Research II, Biomedical Research Foundation of the Academy of Athens, 11527 Athens, Greece.
Sarantis
S
Gagos
Translational Research, Department of Biopathology, Institut Bergonié, 229 cours de l'Argonne, 33076 Bordeaux, France; INSERM U916, 229 cours de l'Argonne, 33076 Bordeaux, France.
Frédéric
F
Chibon
INSERM AVENIR Team, Institute of Human Genetics, CNRS UPR 1142, 141 rue de la Cardonille, 34396 Montpellier, France. Electronic address: jerome.dejardin@igh.cnrs.fr.
Jérôme
J
Déjardin
D002877:Chromosomes, Human / Q000378:metabolism; D053903:DNA Breaks, Double-Stranded; D042822:Genomic Instability; D006801:Humans; D009369:Neoplasms / Q000235:genetics*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D016615:Telomere / Q000378:metabolism*; D035341:Telomeric Repeat Binding Protein 2 / Q000378:metabolism; D014178:Translocation, Genetic
D016194:Receptors, N-Methyl-D-Aspartate; C504753:TERF2 protein, human; D035341:Telomeric Repeat Binding Protein 2