Molecular biology of B cells
The generation of highly specific and adapted humoral responses is achieved by mechanisms initiated by DNA damage inflicted by Activation-induced cytidine deaminase (AID), an enzyme that deaminates cytosines to uracils in DNA. These lesions are processed to introduce mutations in immunoglobulin (Ig) variable regions during somatic hypermutation (SHM) or to generate double stranded DNA break intermediates in Ig switch regions during class switch recombination (CSR). While on-target DNA lesions are crucial for triggering antibody diversification, off-target lesions and/or aberrant DNA repair can initiate malignancy. Although DNA deamination by AID has been clearly established as the mechanism that initiates antibody diversification, the questions of how AID selects its genomic targets and how AID-induced DNA damage is accurately repaired, remain largely unanswered. Our core activity is directed towards elucidation of the molecular mechanisms driving antibody diversification, with a specific focus on the protein complexes involved in mediating AID targeting and in repairing AID-induced DNA damage in vivo.
We would like to increase our knowledge on the molecular mechanisms driving the diversification of the B cell repertoire during immune responses through somatic hypermutation (SHM) and class switch recombination (CSR). Some of the specific questions that we address are:
- How is the function of AID function regulated in vivo ?
- What are the proteins that associate with AID and what is their functional role in CSR and SHM ?
- By which mechanism is the access of AID to chromatin controlled ?
- What is the role of transcription in the genome-wide recruitment of AID ?
- How is AID-induced DNA damage efficiently repaired and why it appears to be differentially regulated at immunoglobulin loci ?
- What are the protein complexes involved in repairing AID-induced DNA damage ?
- What is the molecular defect responsible for the human CSR-specific immunodeficiencies ?
The approaches we use in the laboratory to address these questions include: molecular and cellular techniques, gene targeting/transgenesis in mice, shRNA-mediated knockdown, in vitro cell differentiation assays, protein identification by mass spectrometry, flow cytometry, chromatin immunoprecipitation (ChIP), ChIP-Seq analysis, etc.
- Role of Parp1, Parp2, Parp3 and APLF in immunoglobulin Class Switch Recombination, Françoise Dantzer (ESBS, Illkirch) and Keith W. Caldecott (University of Sussex, UK).
- Transcriptional regulation of the IgH locus, Svend Petersen-Mahrt (IFOM, Italy), Michel Cogné (Université de Limoges, Limoges).
- Mechanisms of DNA repair during CSR,
- Molecular characterization of human CSR-specific immunodeficiencies, Anne Durandy (Hôpital Necker, Paris).
- Ebe SCHIAVO - Thesis Prize of the the Doctoral School in Life and health sciences - Société de Biologie de Strasbourg - 2013
- Bernardo REINA SAN MARTIN - Research Prize - Fondation Schlumberger pour l'Education et la Recherche (FSER) - 2011
- Bernardo REINA SAN MARTIN - Elected member - Henry Kunkel Society - 2010
- Bernardo REINA SAN MARTIN - Scientific Prize - Comité Alsace de la Fondation pour la Recherche Médicale (FRM) - 2009
- Bernardo REINA SAN MARTIN - AVENIR starting grant - Inserm - 2007
- Bernardo REINA SAN MARTIN - Mexican’s National AIDS Research Award - Fondation pour la Recherche Médicale (FRM) - 1995
- July 7, 2016 - Breakdance in mammalian heterochromatin!
- Feb. 22, 2016 - Mediator: Keep me in the loop
- June 15, 2015 - A dual role for Parp3 during immunoglobulin class switch recombination
- Oct. 22, 2013 - To make better antibodies, don’t forget the cohesin complex!
- July 11, 2011 - Better understanding antibodies function to improve vaccine efficiency
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J Exp Med Nov. 18, 2013 ; 210:2495-502 .
J Exp Med July 29, 2013 ; 210:1501-7 .
Mol Aspects Med Dec 2013 ; 34:1138-52 .