title: Rad51 and DNA-PKcs are involved in the generation of specific telomere aberrations induced by the quadruplex ligand 360A that impair mitotic cell progression and lead to cell death.
abstract: Functional telomeres are protected from non-homologous end-joining (NHEJ) and homologous recombination (HR) DNA repair pathways. Replication is a critical period for telomeres because of the requirement for reconstitution of functional protected telomere conformations, a process that involves DNA repair proteins. Using knockdown of DNA-PKcs and Rad51 expression in three different cell lines, we demonstrate the respective involvement of NHEJ and HR in the formation of telomere aberrations induced by the G-quadruplex ligand 360A during or after replication. HR contributed to specific chromatid-type aberrations (telomere losses and doublets) affecting the lagging strand telomeres, whereas DNA-PKcs-dependent NHEJ was responsible for sister telomere fusions as a direct consequence of G-quadruplex formation and/or stabilization induced by 360A on parental telomere G strands. NHEJ and HR activation at telomeres altered mitotic progression in treated cells. In particular, NHEJ-mediated sister telomere fusions were associated with altered metaphase-anaphase transition and anaphase bridges and resulted in cell death during mitosis or early G1. Collectively, these data elucidate specific molecular and cellular mechanisms triggered by telomere targeting by the G-quadruplex ligand 360A, leading to cancer cell death.
authors.affiliation: Laboratoire de Radiopathologie, Institut de Radiobiologie Cellulaire et Moléculaire, CEA, 18 route du Panorama, BP6, 92265, Fontenay-aux-Roses, France.
authors.forename: Laurent R
authors.initials: LR
authors.lastname: Gauthier
authors.forename: Christine
authors.initials: C
authors.lastname: Granotier
authors.forename: Françoise
authors.initials: F
authors.lastname: Hoffschir
authors.forename: Olivier
authors.initials: O
authors.lastname: Etienne
authors.forename: Ali
authors.initials: A
authors.lastname: Ayouaz
authors.forename: Chantal
authors.initials: C
authors.lastname: Desmaze
authors.forename: Patrick
authors.initials: P
authors.lastname: Mailliet
authors.forename: Denis S
authors.initials: DS
authors.lastname: Biard
authors.forename: François D
authors.initials: FD
authors.lastname: Boussin
mesh_terms: D000705:Anaphase; D017209:Apoptosis; D002460:Cell Line; D059766:DNA End-Joining Repair; D051747:DNA-Activated Protein Kinase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D054856:G-Quadruplexes; D059765:Homologous Recombination; D006801:Humans; D008024:Ligands; D008677:Metaphase; D008938:Mitosis / Q000235:genetics*; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology*; D011804:Quinolines / Q000494:pharmacology*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D051135:Rad51 Recombinase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D016615:Telomere / Q000378:metabolism / Q000473:pathology
chemical_list: C502660:2,6-N,N'-methyl-quinolinio-3-yl-pyridine dicarboxamide; D008024:Ligands; D009687:Nuclear Proteins; D011725:Pyridines; D011804:Quinolines; D034741:RNA, Small Interfering; D051747:DNA-Activated Protein Kinase; C497263:PRKDC protein, human; D051135:Rad51 Recombinase