Biomedical subjects

Cécile Caron

Publications and source records attributed to Cécile Caron.

16 recordsLinked to original sources

PubMed2006

Post-meiotic shifts in HSPA2/HSP70.2 chaperone activity during mouse spermatogenesis.

HSPA2 (formerly HSP70.2) is a testis-specific member of the HSP70 family known to play a critical role in the completion of meiosis during male germ cell differentiation. Although abundantly present in post-meiotic cells, its function during spermiogenesis remained obscure. Here, using a global proteomic approach to identify genome-organizing proteins in condensing spermatids, we discovered an unexpected role for HSPA2, which acquires new functions and becomes tightly associated with major spermatid DNA-packaging proteins, transition proteins 1 and 2. Hence, HSPA2 is identified here as the first transition protein chaperone, and these data shed a new light on the yet totally unknown process of genome-condensing structure assembly in spermatids.

Animals↗

PubMed2005

HIV-1 Tat targets Tip60 to impair the apoptotic cell response to genotoxic stresses.

HIV-1 transactivator Tat uses cellular acetylation signalling by targeting several cellular histone acetyltransferases (HAT) to optimize its various functions. Although Tip60 was the first HAT identified to interact with Tat, the biological significance of this interaction has remained obscure. We had previously shown that Tat represses Tip60 HAT activity. Here, a new mechanism of Tip60 neutralization by Tat is described, where Tip60 is identified as a substrate for the newly reported p300/CBP-associated E4-type ubiquitin-ligase activity, and Tat uses this mechanism to induce the polyubiquitination and degradation of Tip60. Tip60 targeting by Tat results in a dramatic impairment of the Tip60-dependent apoptotic cell response to DNA damage. These data reveal yet unknown strategies developed by HIV-1 to increase cell resistance to genotoxic stresses and show a role of Tat as a modulator of cellular protein ubiquitination.

Acetyltransferases↗

PubMed2005

Establishment of male-specific epigenetic information.

The setting of male-specific epigenetic information is a complex process, which involves a major global re-organisation, as well as localized changes of the nucleus structure during the pre-meiotic, meiotic and post-meiotic stages of the male germ cell differentiation. Although it has long been known that DNA methylation in targeted regions of the genome is associated with male-specific genomic imprinting, or that most core histones are hyperacetylated and then replaced by sperm-specific proteins during the post-meiotic condensation of the nucleus, many questions remain unanswered. How these changes interact, how they affect the epigenetic information and how the paternal epigenetic marks contribute to the future genome are indeed major issues remaining to be explored.

Animals↗

PubMed2005

Regulatory cross-talk between lysine acetylation and ubiquitination: role in the control of protein stability.

It is now becoming apparent that cross-talk between two protein lysine modifications, acetylation and ubiquitination, is a critical regulatory mechanism controlling vital cellular functions. The most apparent effect is the inhibition of proteasome-mediated protein degradation by lysine acetylation. Analysis of the underlying mechanisms, however, shows that, besides a direct competition between the two lysine modifications, more complex and indirect processes also connect these two signalling pathways. These findings point to protein lysine acetylation as a potential regulator of various cellular functions involving protein ubiquitination.

Acetylation↗

PubMed2005

How to pack the genome for a safe trip.

The transformation of the somatic chromatin into a unique and highly compact structure occurring during the post-meiotic phase of spermatogenesis is one of the most dramatic known processes of chromatin remodeling. Paradoxically, no information is available on the mechanisms controlling this specific reorganization of the haploid cell genome. The only existing hints suggest a role for histone variants, as well as for stage-specific post-translational histone modifications,before and during the incorporation of testis-specific basic nuclear proteins. Moreover, the exact functions of the latter remain obscure. This chapter summarizes the major chromatin-associated events taking place during the post-meiotic differentiation of male haploid cells in mammals and discusses some of the basic issues that remain to be solved to finally understand chromatin remodeling during spermatogenesis.

Animals↗

PubMed2005

Testis-specific histone H3 expression in somatic cells.

Histone variants functionally differentiate individual nucleosomes and, hence, act as key regulators of chromatin structure and function. Large-scale proteomic projects are now valuable sources of histone-variant discovery, showing, in particular, that somatic mammalian cells express a larger panel of histone H3 variants than previously thought, including testis-specific variants and as yet uncharacterized species. These data also suggest a tight relationship between the complexity of histone-variant expression and physiopathological states of the cells.

Amino Acid Sequence↗

PubMed2005

Cellular uptake of the EBV transcription factor EB1/Zta.

A number of viral proteins have the property to penetrate into the cells when present in the extra-cellular compartment. Here, we report that the Epstein-Barr virus (EBV) transcriptional activator EB1/Zta, which is responsible for the activation of the EBV lytic replication, binds to lymphoid cells surface, is efficiently translocated and accumulates in the nucleus. The internalization of EB1/Zta is energy-dependent and shares common features with endocytosis. As the EB1/Zta was not degraded in the cells and reached the nucleus, the potential effect of its internalisation on viral reactivation was assessed.

B-Lymphocytes↗

PubMed2004

Role of the histone acetyl transferase Tip60 in the p53 pathway.

The histone acetyl transferase Tip60 (HTATIP) shares many properties with the tumor suppressor p53 (TP53). Both proteins are involved in the cellular response to DNA damage, are subjected to proteasomal digestion following Mdm2-mediated ubiquitination, and accumulate after UV irradiation. We found here that knock-down of Tip60 affects the p53-dependent response following actinomycin D treatment, most likely because it inhibits p21 (CDKN1A) accumulation. Moreover, Tip60 is required for p53 to activate the endogenous p21 promoter, suggesting that it functions as a p53 co-activator. However, we also found that knock-down of Tip60 increases the turnover rate of p53 under normal growth conditions. Tip60 interferes with Mdm2-mediated degradation of p53, probably because it affects its subcellular localization. Taken together, our results suggest that Tip60 plays a double role in the p53 pathway: under normal growth conditions, Tip60 contributes to maintain a basal pool of p53 by interfering with its degradation; following DNA damage, Tip60 functions as p53 co-activator. That these two distinct roles are linked during the p53-dependent response is an attractive hypothesis.

Acetyltransferases↗

PubMed2004

The role of histones in chromatin remodelling during mammalian spermiogenesis.

One of the most dramatic chromatin remodelling processes takes place during mammalian spermatogenesis. Indeed, during the postmeiotic maturation of male haploid germ cells, or spermiogenesis, histones are replaced by small basic proteins, which in mammals are transition proteins and protamines. However, nothing is known of the mechanisms controlling the process of histone replacement. Two hints from the literature could help to shed light on the underlying molecular events: one is the massive synthesis of histone variants, including testis-specific members, and the second is a stage specific post-translational modification of histones. A new testis-specific 'histone code' can therefore be generated combining both histone variants and histone post-translational modifications. This review will detail these two phenomena and discuss possible functional significance of the global chromatin alterations occurring prior to histone replacement during spermiogenesis.

Amino Acid Sequence↗

PubMed2004

Functional interaction between class II histone deacetylases and ICP0 of herpes simplex virus type 1.

This study describes the physical and functional interactions between ICP0 of herpes simplex virus type 1 and class II histone deacetylases (HDACs) 4, 5, and 7. Class II HDACs are mainly known for their participation in the control of cell differentiation through the regulation of the activity of the transcription factor MEF2 (myocyte enhancer factor 2), implicated in muscle development and neuronal survival. Immunofluorescence experiments performed on transfected cells showed that ICP0 colocalizes with and reorganizes the nuclear distribution of ectopically expressed class I and II HDACs. In addition, endogenous HDAC4 and at least one of its binding partners, the corepressor protein SMRT (for silencing mediator of retinoid and thyroid receptor), undergo changes in their nuclear distribution in ICP0-transfected cells. As a result, during infection endogenous HDAC4 colocalizes with ICP0. Coimmunoprecipitation and glutathione S-transferase pull-down assays confirmed that class II but not class I HDACs specifically interacted with ICP0 through their amino-terminal regions. This region, which is not conserved in class I HDACs but homologous to the MITR (MEF2-interacting transcription repressor) protein, is responsible for the repression, in a deacetylase-independent manner, of MEF2 by sequestering it under an inactive form in the nucleus. Consequently, we show that ICP0 is able to overcome the HDAC5 amino-terminal- and MITR-induced MEF2A repression in gene reporter assays. This is the first report of a viral protein interacting with and controlling the repressor activity of class II HDACs. We discuss the putative consequences of such an interaction for the biology of the virus both during lytic infection and reactivation from latency.

Animals↗

PubMed2003

Cdyl: a new transcriptional co-repressor.

Cdyl (chromodomain-Y-like) is a chromodomain-containing protein that is predominantly expressed during mouse spermiogenesis. In its carboxy-terminal portion, there is a domain with homology to the coenzyme A (CoA) pocket of the enoyl-CoA hydratase/isomerase, which is shown here to be able to bind CoA and histone deacetylases (HDACs). It also efficiently represses transcription. Moreover, the binding of Hdac1 represses the ability of Cdyl to bind CoA, and a Cdyl-CoA interaction only occurs in the absence of HDACs. These data suggest that Cdyl is primarily a transcriptional co-repressor. However, the degradation of cellular Hdac1 and Hdac2, as observed here in the elongating spermatids, may provide an HDAC-free environment in which Cdyl could bind CoA and participate in the global chromatin remodelling that occurs in these cells.

Amino Acid Sequence↗

PubMed2003

HDAC-6 interacts with and deacetylates tubulin and microtubules in vivo.

Microtubules are cylindrical cytoskeletal structures found in almost all eukaryotic cell types which are involved in a great variety of cellular processes. Reversible acetylation on the epsilon-amino group of alpha-tubulin Lys40 marks stabilized microtubule structures and may contribute to regulating microtubule dynamics. Yet, the enzymes catalysing this acetylation/deacetylation have remained unidentified until recently. Here we report that beta-tubulin interacts with histone deacetylase-6 (HDAC-6) in a yeast two-hybrid assay and in vitro. We find that HDAC-6 is a micro tubule-associated protein capable of deacetylating alpha-tubulin in vivo and in vitro. HDAC-6's microtubule binding and deacetylation functions both depend on the hdac domains. Overexpression of HDAC-6 in mammalian cells leads to tubulin hypoacetylation. In contrast, inhibition of HDAC-6 function by two independent mechanisms--pharmacological (HDAC inhibitors) or genetic (targeted inactivation of HDAC-6 in embryonic stem cells)--leads to hyperacetylation of tubulin and microtubules. Taken together, our data provide evidence that HDAC-6 might act as a dual deacetylase for tubulin and histones, and suggest the possibility that acetylated non-histone proteins might represent novel targets for pharmacological therapy by HDAC inhibitors.

3T3 Cells↗

PubMed2003

The viral control of cellular acetylation signaling.

It is becoming clear that the post-translational modification of histone and non-histone proteins by acetylation is part of an important cellular signaling process controlling a wide variety of functions in both the nucleus and the cytoplasm. Recent investigations designate this signaling pathway as one of the primary targets of viral proteins after infection. Indeed, specific viral proteins have acquired the capacity to interact with cellular acetyltransferases (HATs) and deacetylases (HDACs) and consequently to disrupt normal acetylation signaling pathways, thereby affecting viral and cellular gene expression. Here we review the targeting of cellular HATs and HDACs by viral proteins and highlight different strategies adopted by viruses to control cellular acetylation signaling and to accomplish their life cycle.

Acetyltransferases↗

PubMed2003

Acetylation-dependent chromatin reorganization by BRDT, a testis-specific bromodomain-containing protein.

The association between histone acetylation and replacement observed during spermatogenesis prompted us to consider the testis as a source for potential factors capable of remodelling acetylated chromatin. A systematic search of data banks for open reading frames encoding testis-specific bromodomain-containing proteins focused our attention on BRDT, a testis-specific protein of unknown function containing two bromodomains. BRDT specifically binds hyperacetylated histone H4 tail depending on the integrity of both bromodomains. Moreover, in somatic cells, the ectopic expression of BRDT triggered a dramatic reorganization of the chromatin only after induction of histone hyperacetylation by trichostatin A (TSA). We then defined critical domains of BRDT involved in its activity. Both bromodomains of BRDT, as well as flanking regions, were found indispensable for its histone acetylation-dependent remodelling activity. Interestingly, we also observed that recombinant BRDT was capable of inducing reorganization of the chromatin of isolated nuclei in vitro only when the nuclei were from TSA-treated cells. This assay also allowed us to show that the action of BRDT was ATP independent, suggesting a structural role for the protein in the remodelling of acetylated chromatin. This is the first demonstration of a large-scale reorganization of acetylated chromatin induced by a specific factor.

3T3 Cells↗

PubMed2002

Tip60 acetyltransferase activity is controlled by phosphorylation.

Here we show that the phosphorylation of histone acetyltransferase Tip60, a target of human immunodeficiency virus, type 1-encoded transactivator Tat, plays a crucial role in the control of its catalytic activity. Baculovirus-based expression and purification of Tip60 combined with mass spectrometry allowed the identification of serines 86 and 90 as two major sites of phosphorylation in vivo. The phosphorylation of Tip60 was found to modulate its histone acetyltransferase activity. One of the identified phosphorylated serines, Ser-90, was within a consensus cyclin B/Cdc2 site. Ser-90 was specifically phosphorylated in vitro by the cyclin B/Cdc2 complex. Accordingly, the phosphorylation of Tip60 was enhanced after drug-induced arrest of cells in G(2)/M. This G(2)/M-dependent phosphorylation of Tip60 was abolished by treating cells with a specific inhibitor of the cyclin-dependent kinase, roscovitin. All together, these results strongly suggest a G(2)/M-dependent control of Tip60 activity.

Acetyltransferases↗

PubMed2002

Tat-controlled protein acetylation.

Human immunodeficiency virus, type 1-encoded transactivator protein Tat is known to be a substrate of and to interact with several nuclear histone acetyltransferases (HATs). Here we show that Tat is a general inhibitor of histone acetylation by cellular HATs and that for at least one of them, the CREB-binding protein (CBP), it induces a substrate selectivity. Indeed, in the presence of Tat, the acetylation of histones by CBP was severely inhibited, while that of p53 and MyoD remained unaffected. The C-terminal domain of Tat, dispensable for the activation of viral transcription, was found to be necessary and sufficient to interfere with histone acetylation. These results demonstrate that Tat is able to selectively modulate cellular protein acetylation by nuclear HATs and therefore to take over this specific signaling system in cells.

Acetylation↗