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 |
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Authors: | Laurent?R?Gauthier Chantal?Desmaze Denis?S?Biard Email author" target="_blank">Fran?ois?D?Boussin |
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Affiliation: | 1.Laboratoire de Radiopathologie, Institut de Radiobiologie Cellulaire et Moléculaire,CEA,Fontenay-aux-Roses,France;2.UMR 967,INSERM,Fontenay-aux-Roses,France;3.UMR 967,Université Paris VII,Fontenay-aux-Roses,France;4.UMR 967,Université Paris XI,Fontenay-aux-Roses,France;5.CEA-DSV/iRCM, INSERM U935, Institut A. Lwoff,Villejuif Cedex,France;6.Centre de Recherche de Paris,Sanofi-Aventis,Vitry-sur-Seine,France |
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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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