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Two main research axes are currently being investigated in the lab:
MECHANISMS of DNA recombination
DNA double-strand breaks (DSBs), although common, are extremely dangerous (Deriano and Roth, Annual Review of Genetics, 2013). Unlike most other DNA lesions, DSBs directly threaten genomic integrity by disrupting the physical continuity of the chromosome. A particular threat posed by DSBs arises from repair mechanisms themselves, which, if not executed properly, possess formidable power to wreak genomic havoc. Inappropriate repair of DSBs can cause localized sequence alterations, loss of genomic material, interstitial deletions, inversions, and chromosome translocations, which can initiate neoplastic transformation by a variety of mechanisms. Studies of the repair of physiological DNA double-strand breaks (DSBs) generated by the RAG1/2 enzyme at specific sites during lymphocyte differentiation (i.e. V(D)J recombination) have provided valuable insights into DNA end joining mechanisms. We hypothesize that, in lymphocytes, the RAG complex and the DNA damage response (DDR) machineries co-evolved to promote antigen receptor diversity without conferring predisposition to genomic instability and cell transformation. We use biochemical, genetic, proteomic and cellular approaches to test functional redundancy between the RAG complex and DDR factors in V(D)J recombination and genome stability and to identify novel players of DNA recombination.
FROM physiological DNA rearrangements to lymphoid cancers - LymphoOncoGenomics
B and T cell lymphoid cancers are among the most common human malignancies. Many factors, endogenous and exogenous, are implicated in the etiology of these disorders, but key oncogenic lesions often arise through chromosomal translocations involving antigen receptor loci. These events frequently shows signs of having originated through a variety of errors in RAG1/2 protein-mediated V(D)J recombination. While there are several theoretical possibilities to explain various mechanisms through which such errors occur – lymphocyte development arrest at stages of antigen receptor diversification, recombination errors due to aberrant RAG-, DNA repair-, DDR-activities, etc. –, there has yet to be functional cancer model organisms to test these hypotheses. We use a series of mouse models harboring defects in DNA double strand break regulation, and as a consequence readily develop B- and T-cell tumors. These lymphomas contain numerous genomic aberrations reminiscent of human malignancies. We apply a combination of genomic, transcriptomic, computational and genetic screening approaches to understand the basic nature of genome instability in developing lymphocytes and to identify the genomic lesions and oncogenic pathways underlying lymphomagenesis.
From a general perspective, our studies will provide new insights into the mechanisms of DNA rearrangements, DNA repair, genome stability and tumor biology.
Research Key words
Genome integrity / DNA repair / DNA damage / cancer / immune system / lymphocyte development / V(D)J recombination / non-homologous end joining
Updated on 14/02/2014
Our laboratory is located on the 4th floor of the Bâtiment Metchnikoff (building #67 on the map below), room 4022, on the Institut Pasteur Paris campus.
The nearest subway station is “Pasteur” on the lines 6 and 12.
Ludovic Deriano, Ph.D.
G5 Lymphocyte Development and Oncogenesis
Immunology Department – Metchnikoff building (#67)