Different DNA-PKcs functions in the repair of radiation-induced and spontaneous DSBs within interstitial telomeric sequences

Revaud, Deborah; Martins, L. Miguel; Boussin, François D.; Sabatier, Laure; Desmaze, Chantal

doi:10.1007/s00412-011-0313-1

Cited by 5 publications

(1 citation statement)

References 66 publications

(81 reference statements)

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“…There are several lines of evidence supporting the possible existence of a non-DNA-PKcs-dependent NHEJ pathway [62–65]. It has been proposed that this alternative NHEJ pathway has a predominant role in the formation of chromosome aberrations [65, 66]. However, our data reported here show that this was not the case for 360A-induced sister telomere fusion which involved DNA-PKcs-dependent NHEJ.…”

Section: Discussioncontrasting

confidence: 64%

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

Gauthier

Granotier

Hoffschir

et al. 2011

Cell. Mol. Life Sci.

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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.Electronic supplementary materialThe online version of this article (doi:10.1007/s00018-011-0767-6) contains supplementary material, which is available to authorized users.

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Section: Discussioncontrasting

confidence: 64%

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

Gauthier

Granotier

Hoffschir

et al. 2011

Cell. Mol. Life Sci.

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DNA‐PKcs‐dependent NHEJ pathway supports the progression of topoisomerase II poison‐induced chromosome aberrant cells

Elguero

Campos-Nebel

González-Cid

2012

Environ and Mol Mutagen

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The role of DNA double strand break (DSB) repair pathways, non-homologous end joining (NHEJ), and homologous recombination (HR) was evaluated to prevent the chromosome instability induced by the topoisomerase II (Top2) poisons, idarubicin, and etoposide in Chinese hamster cell lines. XR-C1 (DNA-PKcs deficient) and V-C8 (BRCA2 deficient) showed higher sensitivity to increased concentrations of Top2 poisons compared with their normal counterparts, CHO9 and V79. Both proficient and deficient cells exhibited a marked DSB induction in all phases of the cell cycle. Additionally, deficient cells showed persistent DNA damage 24 hr post-treatment. Chromosomal aberrations increased in the first mitosis following Top2 poison-treatments in G1 or G2 in proficient and deficient cells. CHO9 and V79 demonstrated chromosome and chromatid exchanges following treatments in G1 and G2 phases, respectively. Deficient cells showed high frequencies of chromatid exchanges following treatments in G1 and G2. Simultaneously, we analyzed the micronuclei (MN) induction in interphase cells after treatments in G1, S, or G2 of the previous cell cycle. Both Top2 poisons induced an important increase in MN in CHO9, V79, and V-C8 cells. XR-C1 exhibited an increased MN frequency when cells were treated in G1 phase but not in S or G2. This MN reduction was due to a cell accumulation at G2/M and death in G2-treated cells. Our data suggest that NHEJ and HR operate differentially throughout the cell cycle to protect from Top2 poison-induced chromosome instability, and that DNA-PKcs-dependent NHEJ pathway allows the survival of chromosome damaged cells during S/G2 to the next interphase.

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Bleomycin induces delayed instability of interstitial telomeric sequences in Chinese hamster ovary cells

Bravo

Bianchi

Bolzán

2012

Mutation Research/Fundamental and Molecular Mechanisms of Mutag

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Different DNA-PKcs functions in the repair of radiation-induced and spontaneous DSBs within interstitial telomeric sequences

Cited by 5 publications

References 66 publications

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

DNA‐PKcs‐dependent NHEJ pathway supports the progression of topoisomerase II poison‐induced chromosome aberrant cells

Bleomycin induces delayed instability of interstitial telomeric sequences in Chinese hamster ovary cells

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