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Changeux J.-P.,French National Center for Scientific Research
Nature Reviews Molecular Cell Biology | Year: 2013

The concept of indirect or 'allosteric' interaction between topographically distinct sites, and the subsequent 1965 Monod-Wyman-Changeux (MWC) model for the conformational change mediating them, arose around 50 years ago. Many classic regulatory proteins (including haemoglobin, Asp transcarbamylase and nicotinic acetylcholine receptor) follow the central paradigm of the MWC model, which has been expanded and challenged as a result of novel technologies. Importantly, the concept of allosteric interaction has aided our understanding of human diseases and drug design. © 2013 Macmillan Publishers Limited. All rights reserved.

De Massy B.,French National Center for Scientific Research
Annual Review of Genetics | Year: 2013

Meiotic recombination is essential for fertility in most sexually reproducing species. This process also creates new combinations of alleles and has important consequences for genome evolution. Meiotic recombination is initiated by the formation of DNA double-strand breaks (DSBs), which are repaired by homologous recombination. DSBs are catalyzed by the evolutionarily conserved SPO11 protein, assisted by several other factors. Some of them are absolutely required, whereas others are needed only for full levels of DSB formation and may participate in the regulation of DSB timing and frequency as well as the coordination between DSB formation and repair. The sites where DSBs occur are not randomly distributed in the genome, and remarkably distinct strategies have emerged to control their localization in different species. Here, I review the recent advances in the components required for DSB formation and localization in the various model organisms in which these studies have been performed. © 2013 by Annual Reviews. All rights reserved.

Drane P.,French National Center for Scientific Research
Genes and Development | Year: 2010

The histone variant H3.3 marks active chromatin by replacing the conventional histone H3.1. In this study, we investigate the detailed mechanism of H3.3 replication-independent deposition. We found that the death domain-associated protein DAXX and the chromatin remodeling factor ATRX (α-thalassemia/mental retardation syndrome protein) are specifically associated with the H3.3 deposition machinery. Bacterially expressed DAXX has a marked binding preference for H3.3 and assists the deposition of (H3.3-H4) 2 tetramers on naked DNA, thus showing that DAXX is a H3.3 histone chaperone. In DAXX-depleted cells, a fraction of H3.3 was found associated with the replication-dependent machinery of deposition, suggesting that cells adapt to the depletion. The reintroduced DAXX in these cells colocalizes with H3.3 into the promyelocytic leukemia protein (PML) bodies. Moreover, DAXX associates with pericentric DNA repeats, and modulates the transcription from these repeats through assembly of H3.3 nucleosomes. These findings establish a new link between the PML bodies and the regulation of pericentric DNA repeat chromatin structure. Taken together, our data demonstrate that DAXX functions as a bona fide histone chaperone involved in the replication-independent deposition of H3.3. © 2010 by Cold Spring Harbor Laboratory Press.

Gertner-Dardenne J.,French National Center for Scientific Research
Blood | Year: 2013

Vγ9Vδ2 cells, the major γδ T-cell subset in human peripheral blood, represent a T-cell subset that displays reactivity against microbial agents and tumors. The biology of Vγ9Vδ2 T cells remains poorly understood. We show herein that the interaction between B- and T-lymphocyte attenuator (BTLA) and herpesvirus entry mediator (HVEM) is a major regulator of Vγ9Vδ2 T-cell proliferation control. BTLA was strongly expressed at the surface of resting Vγ9Vδ2 T cells and inversely correlated with T-cell differentiation. BTLA-HVEM blockade by monoclonal antibodies resulted in the enhancement of Vγ9Vδ2 T-cell receptor-mediated signaling, whereas BTLA-HVEM interaction led to a decrease in phosphoantigen-mediated proliferation by inducing a partial S-phase arrest. Our data also suggested that BTLA-HVEM might participate in the control of γδ T-cell differentiation. In addition, the proliferation of autologous γδ T cells after exposition to lymphoma cells was dramatically reduced through BTLA-HVEM interaction. These data suggest that HVEM interaction with BTLA may play a role in lymphomagenesis by interfering with Vγ9Vδ2 T-cell proliferation. Moreover, BTLA stimulation of Vγ9Vδ2 T cells appears as a new possible mechanism of immune escape by lymphoma cells.

Mechali M.,French National Center for Scientific Research
Nature Reviews Molecular Cell Biology | Year: 2010

At each cell division in humans, 30,000-50,000 DNA replication origins are activated, and it remains unclear how they are selected and recognized by replication factors. DNA replication in multicellular organisms must accommodate variations in growth conditions and DNA damage. It must also adapt to changes in chromatin organization associated with cell differentiation and development. The selection of replication origins in metazoans seems to involve multiple choices, with the appropriate answers depending on the identity of the cell or the conditions of growth. This suggests that during evolution, the use of replication origins became more controlled by epigenetic mechanisms affecting chromosome dynamics and expression than by DNA synthesis per se. © 2010 Macmillan Publishers Limited. All rights reserved.

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