UMR3348 – Genome integrity, RNA and Cancer

Unit publications

Year of publication 2018

Marine Fanny Garrido, Nicolas Jp Martin, Matthieu Bertrand, Catherine Gaudin, Frederic Commo, Nassif El Kalaany, Nader Al Nakouzi, Ladan Fazli, Elaine Del Nery, Jacques Camonis, Franck Perez, Stéphanie Lerondel, Alain LE Pape, Martin E Gleave, Yohann Loriot, Laurent Desaubry, Stephan Vagner, Karim Fizazi, Anne Chauchereau (2018 Oct 15)

Regulation of eIF4F translation initiation complex by the peptidyl prolyl isomerase FKBP7 in taxane-resistant prostate cancer.

Clinical cancer research : an official journal of the American Association for Cancer Research : DOI : clincanres.0704.2018 Learn more

Targeted therapies that use the signaling pathways involved in prostate cancer are required to overcome chemoresistance and improve treatment outcomes for men. Molecular chaperones play a key role in the regulation of protein homeostasis and are potential targets for overcoming chemoresistance.

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Year of publication 2017

Michelle Newman, Rym Sfaxi, Abhijit Saha, David Monchaud, Marie-Paule Teulade-Fichou, Stéphan Vagner (2017 Oct 27)

The G-Quadruplex-Specific RNA Helicase DHX36 Regulates p53 Pre-mRNA 3′-End Processing Following UV-Induced DNA Damage.

Journal of Molecular Biology : 429 : 3121-3131 : DOI : 10.1016/j.jmb.2016.11.033 Learn more

Pre-mRNA 3′-end processing, the process through which almost all eukaryotic mRNAs acquire a poly(A) tail is generally inhibited during the cellular DNA damage response leading to a profound impact on the level of protein expression since unprocessed transcripts at the 3′-end will be degraded or unable to be transported to the cytoplasm. However, a compensatory mechanism involving the binding of the hnRNP H/F family of RNA binding proteins to an RNA G-quadruplex (G4) structure located in the vicinity of a polyadenylation site has previously been described to allow the transcript encoding the p53 tumour suppressor protein to be properly processed during DNA damage and to provide the cells with a way to react to DNA damage. Here we report that the DEAH (Asp-Glu-Ala-His) box RNA helicase DHX36/RHAU/G4R1, which specifically binds to and resolves parallel-stranded G4, is necessary to maintain p53 pre-mRNA 3′-end processing following UV-induced DNA damage. DHX36 binds to the p53 RNA G4, while mutation of the G4 impairs the ability of DHX36 to maintain pre-mRNA 3′-end processing. Stabilization of the p53 RNA G4 with two different G4 ligands ((PNA)DOTASQ and PhenDC3), which is expected from previous studies to prevent DHX36 from binding and unwinding G4s, also impairs p53 pre-mRNA 3′-end processing following UV. Our work identifies DHX36 as a new actor in the compensatory mechanisms that are in place to ensure that the mRNAs encoding p53 are still processed following UV.

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Helene Malka-Mahieu, Michelle Newman, Laurent Desaubry, Caroline Robert, Stephan Vagner (2017 Jan 1)

Molecular Pathways: The eIF4F Translation Initiation Complex- New Opportunities for Cancer Treatment.

Clinical cancer research : an official journal of the American Association for Cancer Research : DOI : 10.1158/1078-0432.CCR-14-2362 Learn more

The eIF4F complex regulates the cap-dependent mRNA translation process. It is becoming increasingly evident that aberrant activity of this complex is observed in many cancers leading to the selective synthesis of proteins involved in tumour growth and metastasis. The selective translation of cellular mRNAs controlled by this complex also contributes to resistance to cancer treatments, and downregulation of the eIF4F complex components can restore sensitivity to various cancer therapies. Here we review the contribution of the eIF4F complex to tumourigenesis with a focus on its role in chemoresistance as well as the promising use of new small molecule inhibitors of the complex, including flavaglines/rocaglates, hippuristanol and pateamine A.

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Year of publication 2016

Catharina von Nicolai, Åsa Ehlén, Charlotte Martin, Xiaodong Zhang, Aura Carreira (2016 Sep 15)

A second DNA binding site in human BRCA2 promotes homologous recombination.

Nature communications : 12813 : DOI : 10.1038/ncomms12813 Learn more

BRCA2 tumour-suppressor protein is well known for its role in DNA repair by homologous recombination (HR); assisting the loading of RAD51 recombinase at DNA double-strand breaks. This function is executed by the C-terminal DNA binding domain (CTD) which binds single-stranded (ss)DNA, and the BRC repeats, which bind RAD51 and modulate its assembly onto ssDNA. Paradoxically, analysis of cells resistant to DNA damaging agents missing the CTD restore HR proficiency, suggesting another domain may take over its function. Here, we identify a region in the N terminus of BRCA2 that exhibits DNA binding activity (NTD) and provide evidence for NTD promoting RAD51-mediated HR. A missense variant detected in breast cancer patients located in the NTD impairs HR stimulation on dsDNA/ssDNA junction containing substrates. These findings shed light on the function of the N terminus of BRCA2 and have implications for the evaluation of breast cancer variants.

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Anne Cammas, Magali Lacroix-Triki, Sandra Pierredon, Morgane Le Bras, Jason S Iacovoni, Marie-Paule Teulade-Fichou, Gilles Favre, Henri Roché, Thomas Filleron, Stefania Millevoi, Stéphan Vagner (2016 Mar 29)

hnRNP A1-mediated translational regulation of the G quadruplex-containing RON receptor tyrosine kinase mRNA linked to tumor progression.

Oncotarget : 7 : 16793-16805 : DOI : 10.18632/oncotarget.7589 Learn more

The expression and role of RNA binding proteins (RBPs) controlling mRNA translation during tumor progression remains largely uncharacterized. Analysis by immunohistochemistry of the expression of hnRNP A1, hnRNPH, RBM9/FOX2, SRSF1/ASF/SF2, SRSF2/SC35, SRSF3/SRp20, SRSF7/9G8 in breast tumors shows that the expression of hnRNP A1, but not the other tested RBPs, is associated with metastatic relapse. Strikingly, hnRNP A1, a nuclear splicing regulator, is also present in the cytoplasm of tumor cells of a subset of patients displaying exceedingly worse prognosis. Expression of a cytoplasmic mutant of hnRNP A1 leads to increased translation of the mRNA encoding the tyrosine kinase receptor RON/MTS1R, known for its function in tumor dissemination, and increases cell migration in vitro. hnRNP A1 directly binds to the 5′ untranslated region of the RON mRNA and activates its translation through G-quadruplex RNA secondary structures. The correlation between hnRNP A1 and RON tumoral expression suggests that these findings hold clinical relevance.

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Jeffrey J Nirschl, Maria M Magiera, Jacob E Lazarus, Carsten Janke, Erika L F Holzbaur (2016 Mar 22)

α-Tubulin Tyrosination and CLIP-170 Phosphorylation Regulate the Initiation of Dynein-Driven Transport in Neurons.

Cell reports : 2637-52 : DOI : 10.1016/j.celrep.2016.02.046 Learn more

Motor-cargo recruitment to microtubules is often the rate-limiting step of intracellular transport, and defects in this recruitment can cause neurodegenerative disease. Here, we use in vitro reconstitution assays with single-molecule resolution, live-cell transport assays in primary neurons, computational image analysis, and computer simulations to investigate the factors regulating retrograde transport initiation in the distal axon. We find that phosphorylation of the cytoskeletal-organelle linker protein CLIP-170 and post-translational modifications of the microtubule track combine to precisely control the initiation of retrograde transport. Computer simulations of organelle dynamics in the distal axon indicate that while CLIP-170 primarily regulates the time to microtubule encounter, the tyrosination state of the microtubule lattice regulates the likelihood of binding. These mechanisms interact to control transport initiation in the axon in a manner sensitive to the specialized cytoskeletal architecture of the neuron.

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Chrystelle Aillaud, Christophe Bosc, Yasmina Saoudi, Eric Denarier, Leticia Peris, Laila Sago, Nicolas Taulet, Adeline Cieren, Olivia Tort, Maria M Magiera, Carsten Janke, Virginie Redeker, Annie Andrieux, Marie-Jo Moutin (2016 Feb 15)

Evidence for new C-terminally truncated variants of α- and β-tubulins.

Molecular biology of the cell : 640-53 : DOI : 10.1091/mbc.E15-03-0137 Learn more

Cellular α-tubulin can bear various carboxy-terminal sequences: full-length tubulin arising from gene neosynthesis is tyrosinated, and two truncated variants, corresponding to detyrosinated and Δ2 α‑tubulin, result from the sequential cleavage of one or two C-terminal residues, respectively. Here, by using a novel antibody named 3EG that is highly specific to the -EEEG C-terminal sequence, we demonstrate the occurrence in neuronal tissues of a new αΔ3‑tubulin variant corresponding to α1A/B‑tubulin deleted of its last three residues (EEY). αΔ3‑tubulin has a specific distribution pattern: its quantity in the brain is similar to that of αΔ2-tubulin around birth but is much lower in adult tissue. This truncated α1A/B-tubulin variant can be generated from αΔ2-tubulin by the deglutamylases CCP1, CCP4, CCP5, and CCP6 but not by CCP2 and CCP3. Moreover, using 3EG antibody, we identify a C‑terminally truncated β-tubulin form with the same -EEEG C-terminal sequence. Using mass spectrometry, we demonstrate that β2A/B-tubulin is modified by truncation of the four C-terminal residues (EDEA). We show that this newly identified βΔ4-tubulin is ubiquitously present in cells and tissues and that its level is constant throughout the cell cycle. These new C-terminally truncated α- and β-tubulin variants, both ending with -EEEG sequence, are expected to regulate microtubule physiology. Of interest, the αΔ3-tubulin seems to be related to dynamic microtubules, resembling tyrosinated-tubulin rather than the other truncated variants, and may have critical function(s) in neuronal development.

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Year of publication 2013

Carsten Janke (2013 Oct 16)

Mysterious modification of tubulin.

Nature Reviews Molecular Cell BiologyNature Reviews Molecular Cell Biology Learn more
L Boussemart, E Routier, C Mateus, K Opletalova, G Sebille, N Kamsu-Kom, M Thomas, S Vagner, M Favre, G Tomasic, J Wechsler, L Lacroix, C Robert (2013 Jun 1)

Prospective study of cutaneous side-effects associated with the BRAF inhibitor vemurafenib: a study of 42 patients.

Annals of oncology : official journal of the European Society for Medical Oncology : 1691-7 : DOI : 10.1093/annonc/mdt015 Learn more

BRAF inhibitors are being developed for the treatment of metastatic melanoma harboring a V600E mutation. The use of vemurafenib significantly increases progression-free survival (PFS) and overall survival (OS) in this population of patients, but is associated with numerous adverse skin reactions.

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