4Rs : Replication, Repair, Recombination and ROS

This team belongs to the UMR 9019 Genome Integrity and Cancers.

Our interests focus on understanding the mechanisms that allow the cell to cope with DNA damage and replicative stress. Poorly managed, they are at the origin of genetic instability which is considered to be a major cause of tumor initiation and progression. Both adverse events result either from cellular metabolism or from exposure to various genotoxic agents such as ultraviolet radiations, ionizing radiations, pollutants present in the environment, toxic substances present in products of daily use (tobacco, alcohol), and certain medical treatments such as anti-tumor chemotherapy.

Due to their cytotoxicity, certain agents which induce DNA damage and/or disturb DNA replication, are widely used to cope with the proliferation of cancer cells which, as a rule, have a high replicative activity. So, somewhat paradoxically, the repair and protection of the DNA replication process protects us against cancer, but also allows the tumor cell to better defend itself against radio- or chemotherapy. Therefore understanding how DNA damage is generated and managed by the cell is fundamental to anticipate not only the processes of tumor initiation and progression, but also to anticipate and circumvent the resistance of tumor cells to certain treatments.

In this context, we are interested in the consequences of three sources of genotoxic stress:

• (1) oxidative lesions, generated by the activity of the mitochondria or by the family of NADPH-oxidase NOX/DUOX;
• (2) the DNA interstrand crosslinks, induced by drugs widely used in anti-tumor therapy, such as cis-platinum, melphalan or mitomycin C and
• (3) the replication inhibitors, such as aphidicoline or hydroxyurea.

For our research, we use in vitro cell models, animal models as well as samples taken from patients. We work on thyroid and breast cancer as well as on leukemia. Cells issues from patients with Fanconi Anemia, a rare genetic syndrome predisposing to cancer and leukemia and featuring  cellular and chromosomal hypersensitivity to DNA interstrand crosslinks, oxidative and replicative stress, represent our main genetic model.
Our expertise and experimental approaches range from cellular to molecular biology, including biochemistry, microscopic analysis, and large-scale genomics and proteomics studies.

Major Publications

• Oppezzo A, Bourseguin J, Renaud E, Pawlikowska P, Rosselli F. Microphthalmia transcription factor expression contributes to bone marrow failure in Fanconi anemia. J Clin Invest. 2020, 130:1377-1391.
• Brison O, El-Hilali S, Azar D, Koundrioukoff S, Schmidt M, Nähse V, Jaszczyszyn Y, Lachages AM, Dutrillaux B, Thermes C, Debatisse M, Chen CL. Transcription-mediated organization of the replication initiation program across  large genes sets common fragile sites genome-wide. Nat Commun, 2019, 10:5693.
• Blin M, Le Tallec B, Nähse V, Schmidt M, Brossas C, Millot GA, Prioleau MN, Debatisse M. Transcription-dependent regulation of replication dynamics modulates genome stability. Nat Struct Mol Biol, 2019 26:58-66.
• Leboulleux S, Dupuy C, Lacroix L, Attard M, Grimaldi S, Corre R, Ricard M, Nasr S, Berdelou A, Hadoux J, Hartl D, Terroir M, Baudin E, Schlumberger M, Al Ghuzlan A. Redifferentiation of a BRAFK601E-Mutated Poorly Differentiated Thyroid Cancer Patient with Dabrafenib and Trametinib Treatment. Thyroid, 2019, 29:735-742.
• Renaud, E., A. Barascu, and F. Rosselli. Impaired TIP60-mediated H4K16 acetylation accounts for the aberrant chromatin accumulation of 53BP1 and RAP80 in Fanconi anemia pathway-deficient cells. Nucl Acids Res, 2016, 44:648-656.
• Ameziane-El-Hassani R, Schlumberger M, Dupuy C. NADPH oxidases: new actors in  thyroid cancer? Nat Rev Endocrinol, 2016, 12:485-494.
• Ameziane-El-Hassani R, Talbot M, de Souza Dos Santos MC, Al Ghuzlan A, Hartl D, Bidart JM, De Deken X, Miot F, Diallo I, de Vathaire F, Schlumberger M, Dupuy  C. NADPH oxidase DUOX1 promotes long-term persistence of oxidative stress after an exposure to irradiation. Proc Natl Acad Sci U S A, 2015, 112(16):5051-5056.
• Nguyen, T.V., L. Riou, S. Aoufouchi, and F. Rosselli. Fanca deficiency reduces A/T transitions in somatic hypermutation and alters class switch recombination junctions in mouse B cells. J Exp Med, 2014, 211:1011-1018.
• Pawlikowska, P., P. Fouchet, W. Vainchenker, F. Rosselli, and V. Naim. 2014. Defective endomitosis during megakaryopoiesis leads to thrombocytopenia in Fanca-/- mice. Blood, 2014, 124:3613-3623.
• Naim, V., T. Wilhelm, M. Debatisse, and F. Rosselli. ERCC1 and MUS81-EME1 promote sister chromatid separation by processing late replication intermediates at common fragile sites during mitosis. Nat Cell Biol, 2013, 15:1008-1015.

Lab members

• Filippo Rosselli, DR CNRS, Responsable équipe
• Corinne Dupuy, DR CNRS
• Anne Helbling-Leclerc, MCU Paris Saclay
• Stéphane Koundrioukoff, MCU Paris Saclay
• Camille Buffet, MCU Sourbonne Université
• Jean Feunteun, PU Emerite Paris Saclay
• Michelle Debatisse, PU Emerite Sorbonne Université
• Frédérique Maczkowiak-Chartois, IE CNRS
• Mélanie Schmidt, IE (CDD)
• Pauline Ostyn, Post-doctorante
• Xavier Renaudin, Post-doctorant
• Carlos Fredericos Lima Goncalves, Post-doctorant
• Alessia Oppezzo, Doctorante
• Mickaelle Radom, Doctorante
• Cécile Garcin, M2
• Rahima Khirennas, M2
• Abir Al Ghuzlan, PH Gustave Roussy
• Julien Hadoux, PH Gustave Roussy
• Dana Hartl, PH Gustave Roussy
• Valeria Naim, CRCN Inserm