Ecole doctorale "LOGIQUE DU VIVANT

Ecole Doctorale COMPLEXITE DU VIVANT – Fiche Projet CONCOURS
Nom et prénom du directeur de thèse (et si besoin du co-directeur) : LONDOÑO VALLEJO José Arturo
Le directeur de thèse et le co-directeur doivent impérativement être habilités à diriger les recherches (HDR)
Coordonnées
Tel : 0156246611
e-mail : [email protected]
Nom et prénom du responsable de l’équipe : LONDOÑO VALLEJO José Arturo
Nombre de chercheurs et enseignants-chercheurs statutaires de l’équipe titulaires d’une HDR : 1
Nom et prénom du responsable du laboratoire : LONDOÑO VALLEJO José Arturo
Intitulé du laboratoire et N° d’unité : Dynamique de l’information Génétique. Bases fondamentales et Cancer (DIG-Cancer)
UMR3244
Spécialité : Génomique; Bioinformatique
Titre du projet de thèse : Impact of G-quadruplex structure stabilisation on the human genome
Résumé du projet de thèse (1 page maximum, en anglais)
Nucleic acid G-quadruplex (G4) structures seem to play important biological roles in multiple cellular
processes (telomere maintenance, cellular and viral replication, genome rearrangements, DNA damage
response, epigenetic, transcriptional regulation, etc.). They are scattered throughout the genome and
depending on the algorithms used to identify them in silico their number may reach several hundreds of
thousands. On the other hand, the development of small molecules able to stabilise these structures has
open the possibility of probing and/or interfering with the associated biological processes, thus
emerging as potentially anti-cancer agents. However, the mutagenic potential of both G4 structures and
G4 ligands remains largely uncharacterized. Work in our research unit using human sequences inserted
in the yeast genome has shown that not all G4s display the same potential to induce genome instability
in particular genetic contexts or in response to G4 ligand treatments. These analyses revealed that G4s
carrying very short interconnecting loops between the G runs are more stable in vitro and more
predisposed to undergo instability in vivo. In particular, G4 structures with the consensus
G4N1G4N1G4N1G4 (where N is any nucleotide) and herein called G4L1, carry the higher risk of
instability.
The project proposed here will use bioinformatics approaches 1) To map and annotate G4L1 structures
in the human genome using the consensus and 1000genomes information, as well as available whole
genome sequences in cancer programs (TCGA); and 2) To evaluate, using human cell lines and Next
Generation Sequences approaches, the potential of these sequences to become instable in particular
genetic contexts and in response to treatments with G4 ligands. Commercial (Pyridostatin) and in-house
produced (PhenDC series) G4 ligands will be tested. On the other hand, candidate genes supposed to
prevent G4 instability (helicases such as RTEL1, WRN, BLM) or contribute to their heterogeneity
during evolution or tumorigenesis (APOBEC) will be targeted for dysfunction in the same cell lines.
After treatment, DNA surrounding the G4L1 structures will be captured and analyzed by NGS (up to
800x depth).
The candidate will use bioinformatics tools to carry out tasks 1 and 2. Technicians in their respective
platforms will carry out the experimental aspects of these tasks (cell culture, preparation of libraries and
sequencing).
This project has received the financial support of the Institut Curie PIC3i program.
Thèses actuellement en cours dans l’équipe
Nom et Prénom du doctorant
Nom du directeur de thèse
1
Année de 1ere
inscription et
Ecole Doctorale
Financement pendant la thèse
Ecole Doctorale COMPLEXITE DU VIVANT – Fiche Projet CONCOURS
Trois publications récentes du directeur de thèse (du co-directeur ou du co-encadrant s’il y a lieu).Mettre en gras le nom
du directeur de thèse.
1.
2.
3.
Castro-Vega, L. J., Jouravleva, K., Ortiz-Montero, P., Liu, W. Y., Galeano, J. L., Romero, M., Popova, T.,
Bacchetti, S., Vernot, J. P., and Londono-Vallejo, A. (2015) The senescent microenvironment
promotes the emergence of heterogeneous cancer stem-like cells. Carcinogenesis 36, 1180-1192
Schertzer, M., Jouravleva, K., Perderiset, M., Dingli, F., Loew, D., Le Guen, T., Bardoni, B., de Villartay,
J. P., Revy, P., and Londono-Vallejo, A. (2015) Human regulator of telomere elongation helicase 1
(RTEL1) is required for the nuclear and cytoplasmic trafficking of pre-U2 RNA. Nucleic Acids Res
43, 1834-1847
Castro-Vega, L. J., Jouravleva, K., Liu, W. Y., Martinez, C., Gestraud, P., Hupe, P., Servant, N., Albaud,
B., Gentien, D., Gad, S., Richard, S., Bacchetti, S., and Londono-Vallejo, A. (2013) Telomere crisis in
kidney epithelial cells promotes the acquisition of a microRNA signature retrieved in aggressive
renal cell carcinomas. Carcinogenesis 34, 1173-1180
Docteurs encadrés par le directeur de thèse ayant soutenu après septembre 2010 et publications relatives à leur sujet de thèse.
Mettre en gras le nom du directeur de thèse et celui du docteur.
Nom Prénom : PORRECA Rosa Maria
Date de soutenance : Septembre 2014
Durée de thèse (en mois): 48
Ecole Doctorale : CdV
Publications :
1. Jeitany M, Pineda JR, Liu Q, Porreca RM, Hoffschir F, Desmaze C, Silvestre DC, Mailliet P, Junier MP, LondoñoVallejo A, Ségal-Bendirdjian E, Chneiweiss H, Boussin FD. A preclinical mouse model of glioma with an
alternative mechanism of telomere maintenance (ALT). Int J Cancer. 2015 Apr;136(7):1546-58. doi:
10.1002/ijc.29171. Epub 2014 Sep 11. PubMed PMID: 25175359; PubMed Central PMCID: PMC4303977.
2. Zhdanova NS, Draskovic I, Minina JM, Karamysheva TV, Novo CL, Liu WY, Porreca RM, Gibaud A, Zvereva
ME, Skvortsov DA, Rubtsov NB, Londoño-Vallejo A. Recombinogenic telomeres in diploid Sorex granarius
(Soricidae, Eulipotyphla) fibroblast cells. Mol Cell Biol. 2014 Aug;34(15):2786-99. doi: 10.1128/MCB.01697-13.
Epub 2014 May 19. PubMed PMID: 24842907; PubMed Central PMCID: PMC4135569.
Nom Prénom : Jouravleva Karina
Date de soutenance : 29 septembre 2015
Durée de thèse (en mois): 48
Ecole Doctorale : CdV
Publications :
1.
Castro-Vega, L. J., Jouravleva, K., Ortiz-Montero, P., Liu, W. Y., Galeano, J. L., Romero, M., Popova, T.,
Bacchetti, S., Vernot, J. P., and Londono-Vallejo, A. (2015) The senescent microenvironment promotes the
emergence of heterogeneous cancer stem-like cells. Carcinogenesis 36, 1180-1192
2.
Schertzer, M., Jouravleva, K., Perderiset, M., Dingli, F., Loew, D., Le Guen, T., Bardoni, B., de Villartay, J.
P., Revy, P., and Londono-Vallejo, A. (2015) Human regulator of telomere elongation helicase 1 (RTEL1) is required
for the nuclear and cytoplasmic trafficking of pre-U2 RNA. Nucleic Acids Res 43, 1834-1847
3.
Castro-Vega, L. J., Jouravleva, K., Liu, W. Y., Martinez, C., Gestraud, P., Hupe, P., Servant, N., Albaud, B.,
Gentien, D., Gad, S., Richard, S., Bacchetti, S., and Londono-Vallejo, A. (2013) Telomere crisis in kidney epithelial
cells promotes the acquisition of a microRNA signature retrieved in aggressive renal cell carcinomas. Carcinogenesis
34, 1173-1180
2