UMR3348 – Stress génotoxiques et cancer

Publications de l’unité

Année de publication : 2017

Elie Hatem, Nadine El Banna, Meng-Er Huang (2017 May 24)

Multifaceted roles of glutathione and glutathione-based systems in carcinogenesis and anticancer drug resistance.

Antioxidants & redox signaling : DOI : 10.1089/ars.2017.7134 En savoir plus
Résumé

Glutathione is the most abundant antioxidant molecule in living organisms and has multiple functions. Intracellular glutathione homeostasis, through its synthesis, consumption, and degradation is an intricately balanced process. Glutathione levels are often high in tumor cells prior to treatment and there is a strong correlation between elevated levels of intracellular glutathione/sustained glutathione-mediated redox activity and resistance to pro-oxidant anticancer therapy. Recent Advances: Ample evidence demonstrates that glutathione and glutathione-based systems are particularly relevant in cancer initiation, progression, and the development of anticancer drug resistance.

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Anissia Ait Saada, Ana Teixeira-Silva, Ismail Iraqui, Audrey Costes, Julien Hardy, Giulia Paoletti, Karine Fréon, Sarah A E Lambert (2017 May 4)

Unprotected Replication Forks Are Converted into Mitotic Sister Chromatid Bridges.

Molecular cell : 398-410.e4 : DOI : 10.1016/j.molcel.2017.04.002 En savoir plus
Résumé

Replication stress and mitotic abnormalities are key features of cancer cells. Temporarily paused forks are stabilized by the intra-S phase checkpoint and protected by the association of Rad51, which prevents Mre11-dependent resection. However, if a fork becomes dysfunctional and cannot resume, this terminally arrested fork is rescued by a converging fork to avoid unreplicated parental DNA during mitosis. Alternatively, dysfunctional forks are restarted by homologous recombination. Using fission yeast, we report that Rad52 and the DNA binding activity of Rad51, but not its strand-exchange activity, act to protect terminally arrested forks from unrestrained Exo1-nucleolytic activity. In the absence of recombination proteins, large ssDNA gaps, up to 3 kb long, occur behind terminally arrested forks, preventing efficient fork merging and leading to mitotic sister chromatid bridging. Thus, Rad52 and Rad51 prevent temporarily and terminally arrested forks from degrading and, despite the availability of converging forks, converting to anaphase bridges causing aneuploidy and cell death.

Free acces : authors.elsevier.com/a/1U~li3vVUP2C0m

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Anh Thu Bui, Meng-Er Huang, Maryline Havard, Fanny Laurent-Tchenio, François Dautry, Thierry Tchenio (2017 May 3)

Transient exposure to androgens induces a remarkable self-sustained quiescent state in dispersed prostate cancer cells.

Cell cycle (Georgetown, Tex.) : 879-893 : DOI : 10.1080/15384101.2017.1310345 En savoir plus
Résumé

Cellular quiescence is a reversible cell growth arrest that is often assumed to require a persistence of non-permissive external growth conditions for its maintenance. In this work, we showed that androgen could induce a quiescent state that is self-sustained in a cell-autonomous manner through a « hit and run » mechanism in androgen receptor-expressing prostate cancer cells. This phenomenon required the set-up of a sustained redox imbalance and TGFβ/BMP signaling that were dependent on culturing cells at low density. At medium cell density, androgens failed to induce such a self-sustained quiescent state, which correlated with a lesser induction of cell redox imbalance and oxidative stress markers like CDKN1A. These effects of androgens could be mimicked by transient overexpression of CDKN1A that triggered its own expression and a sustained SMAD phosphorylation in cells cultured at low cell density. Overall, our data suggest that self-sustained but fully reversible quiescent states might constitute a general response of dispersed cancer cells to stress conditions.

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Simon Gemble, Géraldine Buhagiar-Labarchède, Rosine Onclercq-Delic, Christian Jaulin, Mounira Amor-Guéret (2017 May 2)

Cytidine deaminase deficiency impairs sister chromatid disjunction by decreasing PARP-1 activity.

Cell cycle (Georgetown, Tex.) : 1-8 : DOI : 10.1080/15384101.2017.1317413 En savoir plus
Résumé

Bloom Syndrome (BS) is a rare genetic disease characterized by high levels of chromosomal instability and an increase in cancer risk. Cytidine deaminase (CDA) expression is downregulated in BS cells, leading to an excess of cellular dC and dCTP that reduces basal PARP-1 activity, compromising optimal Chk1 activation and reducing the efficiency of downstream checkpoints. This process leads to the accumulation of unreplicated DNA during mitosis and, ultimately, ultrafine anaphase bridge (UFB) formation. BS cells also display incomplete sister chromatid disjunction when depleted of cohesin. Using a combination of fluorescence in situ hybridization and chromosome spreads, we investigated the possible role of CDA deficiency in the incomplete sister chromatid disjunction in cohesin-depleted BS cells. The decrease in basal PARP-1 activity in CDA-deficient cells compromised sister chromatid disjunction in cohesin-depleted cells, regardless of BLM expression status. The observed incomplete sister chromatid disjunction may be due to the accumulation of unreplicated DNA during mitosis in CDA-deficient cells, as reflected in the changes in centromeric DNA structure associated with the decrease in basal PARP-1 activity. Our findings reveal a new function of PARP-1 in sister chromatid disjunction during mitosis.

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