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, Laurent; Granotier, Christine; Hoffschir, Françoise; Étienne, Olivier; Ayouaz, Ali; Desmaze, Chantal; Mailliet, Patrick; Biard, Denis; Boussin, François D.

doi:10.1007/s00018-011-0767-6

Cited by 37 publications

(36 citation statements)

References 69 publications

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“…[12][13][14][15][16][17] 360A, a pyridine derivative, has been shown to target G4 telomeric structures and to impair telomere replication and mitotic progression leading to cell death. [17][18][19]21 While G-quadruplex ligands have been extensively tested in telomerase-positive cells, to our knowledge, no data exist on the effects of these ligands on ALT tumors in vivo. 360A has been previously shown to efficiently reduce the proliferation of telomerase-positive glioma cell lines and SAOS-2 cells in vitro.…”

Section: Discussionmentioning

confidence: 99%

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A preclinical mouse model of glioma with an alternative mechanism of telomere maintenance (ALT)

Jeitany

Pineda

Liu

et al. 2014

Intl Journal of Cancer

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Glioblastoma multiforme is the most aggressive primary tumor of the central nervous system. Glioma stem cells (GSCs), a small population of tumor cells with stem-like properties, are supposedly responsible for glioblastoma multiforme relapse after current therapies. In approximately thirty percent of glioblastoma multiforme tumors, telomeres are not maintained by telomerase but through an alternative mechanism, termed alternative lengthening of telomere (ALT), suggesting potential interest in developing specific therapeutic strategies. However, no preclinical model of ALT glioma was available until the isolation of TG20 cells from a human ALT glioma. Herein, we show that TG20 cells exhibit a high level of telomeric recombination but a stable karyotype, indicating that their telomeres retain their protective function against chromosomal instability. TG20 cells possess all of the characteristic features of GSCs: the expression of neural stem cell markers, the generation of intracerebral tumors in NOD-SCID-IL2Rγ (NSG) mice as well as in nude mice, and the ability to sustain serial intracerebral transplantations without expressing telomerase, demonstrating the stability of the ALT phenotype in vivo. Furthermore, we also demonstrate that 360B, a G-quadruplex ligand of the pyridine derivative series that impairs telomere replication and mitotic progression in cancer cells, prevents the development of TG20 tumors. Together, our results show that intracerebral grafts of TG20 cells in immunodeficient mice constitute an efficient preclinical model of ALT glioblastoma multiforme and that G-quadruplex ligands are a potential therapy for this specific type of tumor.What's new?All cancerous cells share the need to maintain and elongate their telomeres. In approximately 30% of glioblastoma multiforme tumors, telomeres are not maintained by telomerase but through an alternative mechanism, termed ALT, making specific therapeutic strategies potentially interesting. Here, the authors showed that intracerebral grafts of an ALT glioma cell line called TG20 in immunodeficient mice constitute an efficient preclinical model of ALT glioblastoma multiforme, which could aid the understanding of the underlying pathogenesis. This model could also support the development of specific therapies, with the study revealing G-quadruplex ligands as a potential therapy for this specific type of tumor.

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Section: Discussionmentioning

confidence: 99%

“…We showed that intracerebral grafts of TG20 cells represent an efficient preclinical model of ALT glioma that helps reveal the sensitivity of these cells to the G-quadruplex ligand 360B, a more soluble derivative of 360A, known to impair telomere replication and mitotic progression in cancer cells. [17][18][19]…”

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confidence: 99%

A preclinical mouse model of glioma with an alternative mechanism of telomere maintenance (ALT)

Jeitany

Pineda

Liu

et al. 2014

Intl Journal of Cancer

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“…Additionally, a recent report has shown that knockdown of Rad51 protein with shRNA in p53 deficient MEFs or in MEFs with a conditional loss of BRCA2, which is responsible for loading Rad51 onto DNA, resulted in significant erosion of telomeres compared with wildtype cells (Badie et al, 2010). The tight regulation of Rad51 and consequent HR at telomeres, however, is essential for the prevention of chromosomal aberrations stemming from telomere sister chromatid exchanges that are attributed to inappropriate recombination (Gauthier et al, 2011). While it is possible that the Rad51 foci in unchallenged ES cells are associated with telomeres, the fact that many of these Rad51 foci also colocalize with γ-H2AX would suggest that the telomeres are damaged, since γ-H2AX is also used as a marker of uncapped or damaged telomeres (Hao et al, 2004; Nakamura et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

The abundance of Rad51 protein in mouse embryonic stem cells is regulated at multiple levels

Tichy¹,

Pillai²,

Deng³

et al. 2012

Stem Cell Research

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DNA double-strand breaks (DSBs) in embryonic stem (ES) cells are repaired primarily by homologous recombination (HR). The mechanism by which HR is regulated in these cells, however, remains enigmatic. To gain insight into such regulatory mechanisms, we have asked how protein levels of Rad51, a key component of HR, are controlled in mouse ES cells and mouse embryo fibroblasts (MEFs). The Rad51 protein level is about 15-fold higher in ES cells than in MEFs. The level of Rad51 mRNA, however, is only ∼2-fold higher, indicating that the differences in mRNA levels due to rates of transcription or mRNA stability are not sufficient to account for the large difference in the abundance of Rad51 protein. Comparison of Rad51 half-lives between ES cells and MEFs also did not explain the elevated level of Rad51 protein in the ES cells. A comparative assessment of the Rad51 translation level demonstrated that it is translated with much greater efficacy in ES cells than in MEFs. To determine whether this high level of translation in ES cells is a general phenomenon in these cells or whether it is a characteristic of specific proteins, such as those involved with recombination and cell cycle progression, we compared mechanisms that regulate the level of Pcna in ES cells with those that regulate Rad51. The half-life of Pcna and its rate of synthesis were considerably different from those of Rad51 in ES cells, demonstrating that regulation of Rad51 abundance cannot be generalized to other ES cell proteins and not to proteins involved in DNA replication and cell cycle control. Finally, we show that only a small proportion of the abundant Rad51 protein population is activated under basal conditions in ES cells and recruited to DNA DSBs and/or stalled replication forks.

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“…Tumor cells were incubated for 72 hr with or without G‐CSF (100 ng/mL) and 10% fetal bovine serum (FBS), and then were plated in 24‐well plates for 24 hr prior to be imaged through time‐lapse microscopy. Cell migration was recorded for 48 hr (100‐ms exposure time, every 20 min) using an inverted IX81 Olympus microscope (objective 10×/NA 0.30) equipped with a CoolSNAP HQ camera and a cell incubator (5% CO 2 , 19% O 2 and 95% humidity) as described previously . Cell recording was performed in quadruplicate from six random fields (field area, 0.6 mm 2 ) per growth condition using the Metamorph software.…”

Section: Time‐lapse Microscopymentioning

confidence: 99%

“…Cell migration was recorded for 48 hr (100-ms exposure time, every 20 min) using an inverted IX81 Olympus microscope (objective 103/NA 0.30) equipped with a CoolSNAP HQ camera and a cell incubator (5% CO 2 , 19% O 2 and 95% humidity) as described previously. 23 Cell recording was performed in quadruplicate from six random fields (field area, 0.6 mm 2 ) per growth condition using the Metamorph software. Assembling images and cell What's new?…”

Section: Time-lapse Microscopymentioning

confidence: 99%

Granulocyte colony‐stimulating factor off‐target effect on nerve outgrowth promotes prostate cancer development

Dobrenis

Gauthier

Barroca

et al. 2014

Intl Journal of Cancer

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The hematopoietic growth factor granulocyte colony‐stimulating factor (G‐CSF) has a role in proliferation, differentiation and migration of the myeloid lineage and in mobilizing hematopoietic stem and progenitor cells into the bloodstream. However, G‐CSF has been newly characterized as a neurotrophic factor in the brain. We recently uncovered that autonomic nerve development in the tumor microenvironment participates actively in prostate tumorigenesis and metastasis. Here, we found that G‐CSF constrains cancer to grow and progress by, respectively, supporting the survival of sympathetic nerve fibers in 6‐hydroxydopamine‐sympathectomized mice and also, promoting the aberrant outgrowth of parasympathetic nerves in transgenic or xenogeneic prostate tumor models. This provides insight into how neurotrophic growth factors may control tumor neurogenesis and may lead to new antineurogenic therapies for prostate cancer.

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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

Cited by 37 publications

References 69 publications

A preclinical mouse model of glioma with an alternative mechanism of telomere maintenance (ALT)

A preclinical mouse model of glioma with an alternative mechanism of telomere maintenance (ALT)

The abundance of Rad51 protein in mouse embryonic stem cells is regulated at multiple levels

Granulocyte colony‐stimulating factor off‐target effect on nerve outgrowth promotes prostate cancer development

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