Genetic Instability and Cancer

Molecular bases of human diseases

From the earliest stages of tumorigenesis, deregulated oncogenes induce the formation of DNA lesions during the process of DNA replication. Stalled replication forks and chemical alterations in DNA induce a variety of surveillance pathways collectively known as the DNA damage response. Our knowledge of DNA damage signalling and DNA repair mechanisms is well documented by studies that use high doses of laser micro-irradiation, ionizing radiations or endonucleases to induce double-strand DNA breaks in DNA. By contrast, very little is known about how cells respond to DNA replication impediments induced by normal physiological processes such as transcription.

Our objective is to unveil key mechanisms that promote DNA replication under stressful conditions. We believe that these mechanisms are key determinants of tumour growth and resistance to chemotherapies. We use proteomic approaches to understand the biology of the replication machinery under stressful conditions.

We explore novel mechanisms implicated in the signalling of DNA replication stress using an ATR signalling system whereby a defined DNA structure containing a single-stranded DNA gap is used to nucleate, in human cell-free extracts, a singularly active ATR signalling complex that promotes the phosphorylation of endogenous Chk1. We exploit this original system to work out the biochemical principles that underlie the self-assembly and activation of the ATR signalling complex.

We have analysed systematically the composition of replication factories in basal conditions and in response to a variety of replication inhibitors used in chemotherapies. Proteins that determine replication stress responses using different criteria are studied using a combination of biochemical, cell biochemical and DNA fiber labelling approaches.

In recent years, our main focus has been on the molecular function of proteins implicated in Fanconi anaemia, a genetic disorder characterised by congenital abnormalities, bone marrow failure and cancer proneness. FANC proteins are necessary to coordinate the action of molecular machines involved in the rescue of stalled replication forks and in DNA repair.

98
BASBOUS Jihane
Researcher

1115
RIBEYRE Cyril
Researcher

1679
ALGHOUL Emile
PhD Student

1497
LEBDY Rana
PhD Student

1775
MORANO Laura
PhD Student

1921
MEUNIER Loup
Stagiaire

1879
MURCIA Oceane
Stagiaire

PUBLICATIONS OF THE TEAM

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

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

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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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.

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 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.

Rescue of replication failure by Fanconi anaemia proteins.

Constantinou, A

PUBLICATIONS COMMUNES

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
2019 - Nucleic Acids Res 31853544
Service porteur : Genetic Instability and Cancer

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.
2017 - Leukemia , 31, 10, 2104-2113 28186131
Service porteur : Maintenance of genome integrity during DNA replication

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.
2014 - CELL , 156, 1-2, 134-145 24412650
Service porteur : Laboratory of Molecular Virology

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.
2013 - Cell Cycle , 12, 17, 2760-2773 23966156
Service porteur : Maintenance of genome integrity during DNA replication

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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BAPTISTE Julie
BAPTISTE Julie
Sys2Diag
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DUPIN Gaël
DUPIN Gaël
Pôle Emploi
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LARROQUE Marion
LARROQUE Marion
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VRYZAS Dimos
VRYZAS Dimos
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