Dynamics of genetic information : fundamental basis and cancer - Institut Curie / CNRS UMR 3244 / UPMC

Unit Director: Prof. Michelle Debatisse

Keywords: genomic instability, replication, recombination, p53, gene amplification, meiosis

Located on the central Paris campus in the Trouillet-Rossignol building, the unit is composed of five groups, comprising around 25 permanent members (researchers and technicians), and a similar number of postdoctoral researchers and graduate students.

Our research aims to elucidate the regulation of mechanisms crucial to the maintenance of genome integrity, like DNA replication, repair and recombination, and cell cycle checkpoints. Dysfunctions in these processes can cause DNA lesions, in particular DNA double-strand breaks, which are the main source of the chromosome rearrangements typical of cancer cells. They also allow the cell to tolerate these breaks and to propagate unrepaired lesions. We are also interested in identifying how specific cis-acting sequences (tandem repeats, unprotected chromosome ends and common fragile sites, for example) contribute to spontaneous or induced lesions in the genome and subsequent chromosome rearrangements, and how these rearrangements, in turn, modify the pattern of gene expression in tumour cells.

Our experimental models include yeast, mammalian and human cell lines, mutant mouse models and tumour samples. We use a large variety of genetic, molecular and cytogenetic techniques, like fluorescence in situ hybridisation and DNA ‘combing', as well as more global approaches such as DNA microarrays for transcriptome analysis and ChIP-chip mapping of chromatin-associated proteins at sites of DNA lesions.

The five teams in our unit have made many significant contributions to understanding cancer cell biology. Notably, we have demonstrated that:

• Chromosome rearrangements in cancer cells frequently result from cycles of chromosome breakage and fusion (known as breakage–fusion–bridge cycles) initiated at fragile sites (Debatisse team).
• The length of any individual telomere (the structure that protects the end of a chromosome) is heritable and the distribution of telomere lengths in a normal cell affects how the number and the structure of the chromosomes (the karyotype) will change if the cell is transformed (Londono Vallejo team).
• Inhibition of MDM4 (also known as MDMX), a regulator of the tumour suppressor p53, prevents tumour growth (Toledo team).
• Exposure of cells to ionising radiation induces a ‘signature' that is also observed in radiation-induced tumors, a finding that could have important medical and legal applications (Malfoy team).

We have also performed high-resolution genome-wide mapping of DNA double-strand breaks that occur in meiosis and shown that there are ‘hot' and ‘cold' spots for double-strand breaks (Nicolas team).

Group(s):

• Recombination and Genetic Instability
  Group leader: Alain Nicolas
• ARN non codant, épigénétique et fluidité du génome
  Group leader: Antonin Morillon
• Chromosome alterations and Cancer
  Group leader: Bernard Malfoy
• Functional organization and plasticity of mammalian genomes
  Group leader: Prof. Michelle Debatisse
• Genetics of Tumor Suppression
  Group leader: Prof. Franck Toledo
• Telomeres and cancer
  Group leader: José-Arturo Londono Vallejo

Platform(s):

• High-throughput sequencing
  Leader: Alain Nicolas