UMR3348 – Stress génotoxique et cancer

Publications de l’unité

Année de publication : 2017

Alexis Fouquin, Josée Guirouilh-Barbat, Bernard Lopez, Janet Hall, Mounira Amor-Guéret, Vincent Pennaneach (2017 Oct 3)

PARP2 controls double-strand break repair pathway choice by limiting 53BP1 accumulation at DNA damage sites and promoting end-resection.

Nucleic acids research : DOI : 10.1093/nar/gkx881 En savoir plus

Double strand breaks (DSBs) are one of the most toxic lesions to cells. DSB repair by the canonical non-homologous end-joining (C-EJ) pathway involves minor, if any, processing of the broken DNA-ends, whereas the initiation of DNA resection channels the broken-ends toward DNA repair pathways using various lengths of homology. Mechanisms that control the resection initiation are thus central to the regulation to the choice of DSB repair pathway. Therefore, understanding the mechanisms which regulate the initiation of DNA end-resection is of prime importance. Our findings reveal that poly(ADP-ribose) polymerase 2 (PARP2) is involved in DSBR pathway choice independently of its PAR synthesis activity. We show that PARP2 favors repair by homologous recombination (HR), single strand annealing (SSA) and alternative-end joining (A-EJ) rather than the C-EJ pathway and increases the deletion sizes at A-EJ junctions. We demonstrate that PARP2 specifically limits the accumulation of the resection barrier factor 53BP1 at DNA damage sites, allowing efficient CtIP-dependent DNA end-resection. Collectively, we have identified a new PARP2 function, independent of its PAR synthesis activity, which directs DSBs toward resection-dependent repair pathways.

Elias Bou Samra, Géraldine Buhagiar-Labarchède, Christelle Machon, Jérôme Guitton, Rosine Onclercq-Delic, Michael R Green, Olivier Alibert, Claude Gazin, Xavier Veaute, Mounira Amor-Guéret (2017 Sep 27)

A role for Tau protein in maintaining ribosomal DNA stability and cytidine deaminase-deficient cell survival.

Nature communications : 693 : DOI : 10.1038/s41467-017-00633-1 En savoir plus

Cells from Bloom’s syndrome patients display genome instability due to a defective BLM and the downregulation of cytidine deaminase. Here, we use a genome-wide RNAi-synthetic lethal screen and transcriptomic profiling to identify genes enabling BLM-deficient and/or cytidine deaminase-deficient cells to tolerate constitutive DNA damage and replication stress. We found a synthetic lethal interaction between cytidine deaminase and microtubule-associated protein Tau deficiencies. Tau is overexpressed in cytidine deaminase-deficient cells, and its depletion worsens genome instability, compromising cell survival. Tau is recruited, along with upstream-binding factor, to ribosomal DNA loci. Tau downregulation decreases upstream binding factor recruitment, ribosomal RNA synthesis, ribonucleotide levels, and affects ribosomal DNA stability, leading to the formation of a new subclass of human ribosomal ultrafine anaphase bridges. We describe here Tau functions in maintaining survival of cytidine deaminase-deficient cells, and ribosomal DNA transcription and stability. Moreover, our findings for cancer tissues presenting concomitant cytidine deaminase underexpression and Tau upregulation open up new possibilities for anti-cancer treatment.Cytidine deaminase (CDA) deficiency leads to genome instability. Here the authors find a synthetic lethal interaction between CDA and the microtubule-associated protein Tau deficiencies, and report that Tau depletion affects rRNA synthesis, ribonucleotide pool balance, and rDNA stability.

Sudarshan Gadadhar, Hala Dadi, Satish Bodakuntla, Anne Schnitzler, Ivan Bièche, Filippo Rusconi, Carsten Janke (2017 Sep 4)

Tubulin glycylation controls primary cilia length.

The Journal of cell biology : 2701-2713 : DOI : 10.1083/jcb.201612050 En savoir plus

As essential components of the eukaryotic cytoskeleton, microtubules fulfill a variety of functions that can be temporally and spatially controlled by tubulin posttranslational modifications. Tubulin glycylation has so far been mostly found on motile cilia and flagella, where it is involved in the stabilization of the axoneme. In contrast, barely anything is known about the role of glycylation in primary cilia because of limitations in detecting this modification in these organelles. We thus developed novel glycylation-specific antibodies with which we detected glycylation in many primary cilia. Glycylation accumulates in primary cilia in a length-dependent manner, and depletion or overexpression of glycylating enzymes modulates the length of primary cilia in cultured cells. This strongly suggests that glycylation is essential for the homeostasis of primary cilia, which has important implications for human disorders related to primary cilia dysfunctions, such as ciliopathies and certain types of cancer.

Richard Belvindrah, Kathiresan Natarajan, Preety Shabajee, Elodie Bruel-Jungerman, Jennifer Bernard, Marie Goutierre, Imane Moutkine, Xavier H Jaglin, Mythili Savariradjane, Theano Irinopoulou, Jean-Christophe Poncer, Carsten Janke, Fiona Francis (2017 Aug 7)

Mutation of the α-tubulin Tuba1a leads to straighter microtubules and perturbs neuronal migration.

The Journal of cell biology : 2443-2461 : DOI : 10.1083/jcb.201607074 En savoir plus

Brain development involves extensive migration of neurons. Microtubules (MTs) are key cellular effectors of neuronal displacement that are assembled from α/β-tubulin heterodimers. Mutation of the α-tubulin isotype TUBA1A is associated with cortical malformations in humans. In this study, we provide detailed in vivo and in vitro analyses of Tuba1a mutants. In mice carrying a Tuba1a missense mutation (S140G), neurons accumulate, and glial cells are dispersed along the rostral migratory stream in postnatal and adult brains. Live imaging of Tuba1a-mutant neurons revealed slowed migration and increased neuronal branching, which correlated with directionality alterations and perturbed nucleus-centrosome (N-C) coupling. Tuba1a mutation led to increased straightness of newly polymerized MTs, and structural modeling data suggest a conformational change in the α/β-tubulin heterodimer. We show that Tuba8, another α-tubulin isotype previously associated with cortical malformations, has altered function compared with Tuba1a. Our work shows that Tuba1a plays an essential, noncompensated role in neuronal saltatory migration in vivo and highlights the importance of MT flexibility in N-C coupling and neuronal-branching regulation during neuronal migration.