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.

Jihane BASBOUS
Researcher

0434359815
Angelos CONSTANTINOU
Researcher

0434359814 / 0434359907
Dana HODROJ
Researcher
Researcher

0434359973
Tom Egger
Tom EGGER
IT

0434359973
Emile Alghoul
Emile ALGHOUL
PhD Student

0434359815
Elia Moarbess
Elia MOARBESS
PhD Student
PhD Student

0434359815
Laura Morano
Laura MORANO
PhD Student

0434359815
Zoé Feurer
Zoé FEURER
Stagiaire

0434359815

PUBLICATIONS OF THE TEAM

An optogenetic proximity labeling approach to probe the composition of inducible biomolecular condensates in cultured cells.

Alghoul E, Basbous J, Constantinou A

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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

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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

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.

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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

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

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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

+ Maintenance of genome integrity during DNA replication

DNA structure-specific priming of ATR activation by DNA-PKcs

Vidal-Eychenié S, Décaillet C, Basbous J, Constantinou A.

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 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

Rescue of replication failure by Fanconi anaemia proteins.

Constantinou, A

KUMBHAR Ramhari
KUMBHAR Ramhari
University of Texas at Austin, USA
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PROMONET Alexy
PROMONET Alexy
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CHAUVIN Maëva
CHAUVIN Maëva
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GERUS-DURAND Marie
GERUS-DURAND Marie
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NASSOUR Elie
NASSOUR Elie
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ZADDAM Walid
ZADDAM Walid
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BAPTISTE Julie
BAPTISTE Julie
Sys2Diag
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FRATTINI Camilla
FRATTINI Camilla
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DUPIN Gaël
DUPIN Gaël
Pôle Emploi
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PATOUILLARD Julie
PATOUILLARD Julie
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LEBDY Rana
LEBDY Rana
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LAMARQUE Marie
LAMARQUE Marie
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HADDAD Eugenia
HADDAD Eugenia
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HERAULT Florian
HERAULT Florian
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LARROQUE Marion
LARROQUE Marion
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KASSOUF Toufic
KASSOUF Toufic
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REBILLARD Pauline
REBILLARD Pauline
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VRYZAS Dimos
VRYZAS Dimos
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HOGEDE Alexandra
HOGEDE Alexandra
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HASAN Ali
HASAN Ali
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AMMAR Josiane
AMMAR Josiane
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Topic: Compartmentalization of replicative stress tolerance mechanisms by FA/BRCA pathway proteins
Emile ALGHOUL
- Since 4/11/2019
Supervisor: Angelos CONSTANTINOU - Co-supervisor: Jihane BASBOUS

Subject: Targeting DNA damage-induced TopBP1 nuclear foci to overcome chemotherapy resistance in colorectal cancer
Laura MORANO
- Since 4/12/2020
Supervisor: Angelos CONSTANTINOU

Future thesis (2022) funded by ANR:
Mechanisms, regulation and biological functions of TopBP1 condensates