1. Academic Validation
  2. 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

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

  • Cell Mol Life Sci. 2012 Feb;69(4):629-40. doi: 10.1007/s00018-011-0767-6.
Laurent R Gauthier 1 Christine Granotier Françoise Hoffschir Olivier Etienne Ali Ayouaz Chantal Desmaze Patrick Mailliet Denis S Biard François D Boussin
Affiliations

Affiliation

  • 1 Laboratoire de Radiopathologie, Institut de Radiobiologie Cellulaire et Moléculaire, CEA, 18 route du Panorama, BP6, 92265, Fontenay-aux-Roses, France.
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.

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