Erika BRUNET and Patrick REVY

Genomic dynamics is a fundamental aspect of biological diversity throughout evolution and is clearly accompanied by powerful mechanisms for the control and repair of DNA damage (DDR), particularly double-strand breaks (DSBs), which are the most toxic. The effectiveness of the DDR is essential to ensure that genomic dynamics do not give rise to genomic instability, which is a precursor to a range of diseases.

The DGSI team is dedicated to understanding the consequences of DNA repair defects in human diseases, particularly those linked to the immuno-haematological system but also to certain rare childhood cancers. In particular, V(D)J recombination—a molecular mechanism essential for the development of the adaptive immune system—contributes, through precise chromosomal rearrangements, to the generation of the antigenic repertoires of T and B lymphocytes. Research into V(D)J recombination disorders has, in particular, led to the identification of most of the factors involved in the non-homologous end-joining (NHEJ) repair pathway. All of these repair factors, including Artemis—a gene identified by the team in 2001 (Moshous et al, Cell 2001)—belong to the class of genetic integrity guardians (caretakers). Mutations in the proteins responsible for maintaining genomic integrity are implicated in rare diseases, including immunodeficiencies and telomeropathies (such as congenital dyskeratosis or Hoyeraal–Hreidarsson syndromes), but are also directly involved in the development of rare paediatric cancers.

Our team is developing four complementary research projects centred on this theme, each led by a researcher and their group within the team:

1. Understanding the regulatory mechanisms of cdbDNA, particularly in V(D)J recombination, and the search for biomarkers associated with cdbDNA-related diseases (JP.De Villartay)
2. Studies of telomeropathies and ribosomopathies (P. Revy)
3. Studies into the mechanisms of genomic instability and modelling of rare paediatric lymphomas and sarcomas using CRISPR/Cas9 (and other ‘genome editing' methods) (E. Brunet)
4. Identification of the genetic causes of immunodeficiencies and other DNA-related disorders (D. Moshous)