Compartmentalization of the DNA damage response: Mechanisms and functions
ALGHOUL Emile, BASBOUS Jihane, CONSTANTINOU Angelos
Genetic Instability and Cancer
Molecular bases of human diseases
DNA repair mechanisms are crucial for organismal health and survival. Therefore, all living organisms have evolved diverse mechanisms to repair alterations in the primary structure of DNA. Inherited defects in the mechanisms of genome maintenance is the underlying cause of cancer prone disorders such as Fanconi anemia, a disease characterized by defects in the repair of inter-strand DNA crosslinks and in the rescue of stalled replication forks. Furthermore, metabolic rewiring associated with carcinogenesis induces DNA lesions. Therefore, cancer cells rely on DNA damage responses to sustain growth in the presence of a high load of endogenous lesions and during chemotherapeutic treatments.
Our objective is to understand the biochemical mechanisms that underpin cellular responses to DNA lesions. These mechanisms are determinants for tumor growth and resistance to chemotherapies. We have analyzed systematically the protein composition of replication sites in basal conditions and in response to a variety of chemotherapeutic agents to identify proteins that ensure the progression of replication forks.
In recent years, our main focus has been on the mechanisms and functions of compartmentalization in the DNA damage response (DDR). Proteins required for the detection, the signaling and the repair of DNA lesions typically accumulate within distinct nuclear sites visualized as foci by immunofluorescence staining. We consider DDR nuclear foci as membrane-less compartments that control the spaciotemporal organization of DNA damage responses.
Our working model is that the recruitment of a key multivalent protein scaffolds at DNA lesions nucleates the assembly of DDR foci. Foci formation is triggered by posttranslational modifications that increase attractive interactions. These cooperative and reversible interactions promote the formation of micron-sized protein networks that fulfill the functions of subcellular compartments. For example, we reported recently that the multivalent protein scaffold TOPBP1 drives the assembly of nuclear foci to activate ATR/Chk1 signaling.
We use a combination of molecular biology, biochemistry, optogenetics and high-resolution microscopy to understand the mechanisms, the internal organization and the functions that arise specifically from the assembly of membrane-less compartments in the DDR.
Publications of the team
Compartmentalization of the SUMO/RNF4 pathway by SLX4 drives DNA repair
Emile Alghoul, Matteo Paloni, Arato Takedachi, Serge Urbach, Alessandro Barducci, Pierre-Henri Gaillard, Jihane Basbous, Angelos Constantinou
The BLM helicase is a new therapeutic target in multiple myeloma involved in replication stress survival and drug resistance.
Ovejero S, Viziteu E, Dutrieux L, Devin J, Lin YL, Alaterre E, Jourdan M, Basbous J, Requirand G, Robert N, de Boussac H, Seckinger A, Hose D, Vincent L, Herbaux C, Constantinou A, Pasero P, Moreaux J
+
Epigenome modifications and genomic instability in normal and malignant B cells
Replication gap suppression depends on the double-strand DNA binding activity of BRCA2
Domagoj Vugic, Isaac Dumoulin, Charlotte Martin, Anna Minello, Lucia Alvaro-Aranda, Jesus Gomez-Escudero , Rady Chaaban , Rana Lebdy , Catharina von Nicolai , Virginie Boucherit , Cyril Ribeyre , Angelos Constantinou, Aura Carreira
An optogenetic proximity labeling approach to probe the composition of inducible biomolecular condensates in cultured cells.
Alghoul E, Basbous J, Constantinou A
TopBP1 assembles nuclear condensates to switch on ATR signaling.
Frattini C, Promonet A, Alghoul E, Vidal-Eychenie S, Lamarque M, Blanchard MP, Urbach S, Basbous J, Constantinou A
Dihydropyrimidinase protects from DNA replication stress caused by cytotoxic metabolites.
Basbous J, Aze A, Chaloin L, Lebdy R, Hodroj D, Ribeyre C, Larroque M, Shepard C, Kim B, Pruvost A, Moreaux J, Maiorano D, Mechali M, Constantinou A
+
Genetic Instability and Cancer
Dihydropyrimidinase protects from DNA replication stress caused by cytotoxic metabolites.
Basbous J, Aze A, Chaloin L, Lebdy R, Hodroj D, Ribeyre C, Larroque M, Shepard C, Kim B, Pruvost A, Moreaux J, Maiorano D, Mechali M, Constantinou A
+
Genetic Instability and Cancer
A tumor suppressive DNA translocase named FANCM.
Basbous J, Constantinou A
Recruitment of ubiquitin-activating enzyme UBA1 to DNA by poly(ADP-ribose) promotes ATR signalling.
Kumbhar R, Vidal-Eychenié S, Kontopoulos DG, Larroque M, Larroque C, Basbous J, Kossida S, Ribeyre C, Constantinou A
+ IMGT® - the international ImMunoGeneTics information system®
RECQ1 helicase is involved in replication stress survival and drug resistance in multiple myeloma
Viziteu E, Klein B, Basbous J, Lin YL, Hirtz C, Gourzones C, Tiers L, Bruyer A, Vincent L, Grandmougin C, Seckinger A, Goldschmidt H, Constantinou A, Pasero P, Hose D, Moreaux J.
+
Maintenance of genome integrity during DNA replication
Fanconi anemia FANCD2 and FANCI proteins regulate the nuclear dynamics of splicing factors
Moriel-Carretero, M., Ovejero, S., Gerus-Durand, M., Vryzas, D., Constantinou, A.
Nascent DNA Proteomics Reveals a Chromatin Remodeler Required for Topoisomerase I Loading at Replication Forks
Ribeyre C, Zellweger R, Chauvin M, Bec N, Larroque C, Lopes M, Constantinou A
Cancer-associated SF3B1 mutations affect alternative splicing by promoting alternative branchpoint usage
Alsafadi S, Houy A, Battistella A, Popova T, Wassef M, Henry E, Tirode F, Constantinou A, Piperno-Neumann S, Roman-Roman S, Dutertre M, Stern MH
DNA repair in diffuse large B-cell lymphoma: a molecular portrait
Bret C, Klein B, Cartron G, Schved JF, Constantinou A, Pasero P, Moreaux J.
Premature Activation of the SLX4 Complex by Vpr Promotes G2/M Arrest and Escape from Innate Immune Sensing
Laguette,N., Bregnard, C., Hue, P., Basbous, J., Yatim, A., Larroque, M., Kirchhoff, F., Constantinou, A., Sobhian, B., Benkirane, M.
A DNA repair pathway score predicts survival in human multiple myeloma: the potential for therapeutic strategy
Kassambara A, Gourzones-Dmitriev C, Sahota S, Rème T, Moreaux J, Goldschmidt H, Constantinou A, Pasero P, Hose D, Klein B
DNA repair pathways in human multiple myeloma: Role in oncogenesis and potential targets for treatment.
Gourzones-Dmitriev C, Kassambara A, Sahota S, Rème T, Moreaux J, Bourquard P, Hose D, Pasero P, Constantinou A, Klein B.
+
Maintenance of genome integrity during DNA replication
FANCD2 Binds MCM Proteins and Controls Replisome Function upon Activation of S Phase Checkpoint Signaling.
Lossaint G, Larroque M, Ribeyre C, Bec N, Larroque C, Décaillet C, Gari K, Constantinou A.
DNA structure-specific priming of ATR activation by DNA-PKcs
Vidal-Eychenié S, Décaillet C, Basbous J, Constantinou A.
Rescue of replication failure by Fanconi anaemia proteins.
Constantinou, A
Thèses et hdr
Characterization of a Novel Role of LNG3 in the Maintenance of Genome Stability 18/03/2022
Defended by Rana Lebdy on 18/03/2022 under the supervision of Cyril Ribeyre
HDR 02/12/2021
Role of protein condensation in response to DNA damage
By Jihane Basbous the 02/12/2021
Ubiquitylation mechanisms in the response to DNA damage 16/09/2016
Defended by Ramhari Kumbhar on 16/09/2016 under the supervision of Angelos Constantinou and Cyril Ribeyre, Montpellier
