4Rs : Replication, Repair, Recombination and ROS

Team leader
Filippo Rosselli

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4Rs : Replication, Repair, Recombination and ROS

4Rs : Replication, Repair, Recombination and ROS

This group 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.



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