Genome stability
Carl MANN
CEA Saclay/Bât 142
Tél: 01 69 08 92 94
carl.mann@cea.fr
CEA Saclay/Bât 142
Tél: 01 69 08 92 94
carl.mann@cea.fr
iBiTec-S / SBIGeM / LSOC
Human resources
Carl MANN, Group leader
Jean-Yves THURET, Researcher
Régis COURBEYRETTE , Research Technician
Claudia GEY, Postdoctoral Fellow
Yue JIAO, PhD Student
Research Programs
Studies the mechanisms ensuring genomic stability at the level of chromatin and the cellular response to genotoxic stress.
Our group studies the molecular mechanisms maintaining genome stability in eukaryotes at the level of chromatin and the response to genotoxic stress. Several pathways are implicated in the faithful duplication and segregation of the genome assembled into chromatin, and checkpoint pathways verify the proper progression of these processes in order to induce cellular senescence or apoptosis in cells having suffered excessive genomic damage that would increase the risk of cancer. We have been working at the interface of chromatin and genome stability for the past several years. We have been characterizing histone chaperones that are implicated in the response to genotoxic stress and in the formation of repressive heterochromatin in yeast and in mammals. We work in close collaboration with the Structural Radiobiology group directed by Françoise Ochsenbein and Raphaël Guerois (iBiTec-S/SB2SM). Asf1 is a chaperone of histones H3/H4 that interacts with several others partners including DNA checkpoint kinases. We established a primordial role for the Asf1-H3 interaction in the response to genotoxic stress and transcriptional silencing in yeast. An important role for this interaction is to promote acetylation of H3-K56. The role of this acetylation is poorly understood. We would like to better understand how Asf1 contributes to the cellular resistance to DNA damage and whether these functions are conserved in mammals. Finally, we are also interested in determining the role of the interaction of Asf1 with DNA checkpoint kinases.
Through the direct visualization of H3-GFP fusion proteins in Hela cells and FRAP (Fluorescence Recovery After Photobleaching) analyses, we established a critical role for the Asf1-H3 interaction in the efficient deposition of histones H3.1 (coupled to DNA replication) and H3.3 (independent of DNA replication) in living human cells. Currently, we are studying the formation of senescent-associated heterochromatic foci. Histone chaperons are implicated in the formation of this heterochromatin that leads the quasi-irreversible repression of genes required for cell proliferation when mammalian cells are subjected to genotoxic stress, including the expression of oncogenes that can induce DNA lesions. The induction of cellular senescence after oncogene expression acts as an important tumor suppression mechanism.
©CEA/C Mann, JY Thuret
Publications
Galvani A, Courbeyrette R, Agez M, Ochsenbein F, Mann C, Thuret JY. (2008). In vivo study of the nucleosome assembly functions of ASF1 histone chaperones in human cells. Mol Cell Biol. 28, 3672-85.
Mousson F, Ochsenbein F, Mann C. (2007). The histone chaperone Asf1 at the crossroads of chromatin and DNA checkpoint pathways. Chromosoma. 116, 79-93.
Agez M, Chen J, Guerois R, van Heijenoort C, Thuret JY, Mann C, Ochsenbein F. (2007). Structure of the histone chaperone asf1 bound to the histone h3 C-terminal helix and functional insights Structure Structure. 15, 191-199.
Oliva-Trastoy M, Berthonaud V, Chevalier A, Ducrot C, Marsolier-Kergoat MC, Mann C, Leteurtre F. (2007). The Wip1 phosphatase (PPM1D) antagonizes activation of the Chk2 tumour suppressor kinase. Oncogene. 26, 1449-1458.
Kisseleva-Romanova E, Lopreiato R, Baudin-Baillieu A, Rousselle JC, Ilan L, Hofmann K, Namane A, Mann C, Libri D. (2006) Yeast homolog of a cancer-testis antigen defines a new transcription complex. EMBO J. 9, 3576-85.
Dubacq C, Chevalier A, Courbeyrette R, Petat C, Gidrol X, Mann C. (2006). Role of the iron mobilization and oxidative stress regulons in the genomic response of yeast to hydroxyurea. Mol Genet Genomics. 275, 114-124.
Thuret JY, Blondel M. (2006). Ready for an orange revolution in biotechnology? Biotechnol J. 1, 237-238.
Mousson F, Lautrette A, Thuret JY, Agez M, Courbeyrette R, Amigues B, Becker E, Neumann JM, Guerois R, Mann C, Ochsenbein F. (2005). Structural basis for the interaction of Asf1 with histone H3 and its functional implications Proc Natl Acad Sci U S A. 102, 5975-5980.
Mousson F, Couprie J, Thuret JY, Neumann JM, Mann C, Ochsenbein F. (2004). 1H, 13C and 15N resonance assignments of the conserved core of hAsf1 A. J Biomol NMR. 29, 413-414.
Dubacq C, Chevalier A, Mann C. (2004). The protein kinase snf1 is required for tolerance to the ribonucleotide reductase inhibitor hydroxyurea Mol Cell Biol. 24, 2560-2572.
Badin-Larcon AC, Boscheron C, Soleilhac JM, Piel M, Mann C, Denarier E, Fourest-Lieuvin A, Lafanechere L, Bornens M, Job D. (2004). Suppression of nuclear oscillations in Saccharomyces cerevisiae expressing Glu tubulin. Proc Natl Acad Sci U S A. 101, 5577-5582.
Le Masson I, Yu DY, Jensen K, Chevalier A, Courbeyrette R, Boulard Y, Smith MM, Mann C. (2003). Yaf9, a novel NuA4 histone acetyltransferase subunit, is required for the cellular response to spindle stress in yeast. Mol Cell Biol. 23, 6086-6102.
Le Masson I, Saveanu C, Chevalier A, Namane A, Gobin R, Fromont-Racine M, Jacquier A, Mann C. (2002). Spc24 interacts with Mps2 and is required for chromosome segregation, but is not implicated in spindle pole body duplication. Mol Microbiol. 43, 1431-1443.
Dubacq C, Guerois R, Courbeyrette R, Kitagawa K, Mann C. (2002). Sgt1p contributes to cyclic AMP pathway activity and physically interacts with theadenylyl cyclase Cyr1p/Cdc35p in budding yeast. Eukaryot Cell. 1, 568-582.
Miled C, Mann C, Faye G. (2001). Xbp1-mediated repression of CLB gene expression contributes to the modification of yeast cell morphology and cell cycle seen during nitrogen-limited growth. Mol Cell Biol. 21, 3714-3724.
Leroy C, Mann C, Marsolier MC. (2001). Silent repair accounts for cell cycle specificity in the signalling of oxidative DNA lesions. EMBO J. 20, 2896-2906.
Hermand D, Westerling T, Pihlak A, Thuret JY, Vallenius T, Tiainen M, Vandenhaute J, Cottarel G, Mann C, Mäkelä TP. (2001). Specificity of Cdk activation in vivo by the two Caks Mcs6 and Csk1 in fission yeast EMBO J. 20, 82-90.
Ceccarelli E, Mann C. (2001). A Cdc28 mutant uncouples G1 cyclin phosphorylation and ubiquitination from G1 cyclin proteolysis. J Biol Chem. 276, 41725-41732.
Marsolier MC, Roussel P, Leroy C, Mann C. (2000). Involvement of the PP2C-like phosphatase Ptc2p in the DNA checkpoint pathways of Saccharomyces cerevisiae. Genetics. 154, 1523-1532.
Marcand S, Brevet V, Mann C, Gilson E. (2000). Cell cycle restriction of telomere elongation Curr Biol. 10, 487-490.
Bouquin N, Barral Y, Courbeyrette R, Blondel M, Snyder M, Mann C. (2000). Regulation of cytokinesis by the Elm1 protein kinase in Saccharomyces cerevisiae. J Cell Sci. 113, 1435-1445.
Muñoz-Centeno MC, McBratney S, Monterrosa A, Byers B, Mann C, Winey M. (1999). Saccharomyces cerevisiae MPS2 encodes a membrane protein localized at the spindle pole body and the nuclear envelope. Mol Biol Cell. 10, 2393-2406
Thuret JY, Mann C. (1998). In vivo veritas. Med Sci. 14, 215-218.
Mousson F, Ochsenbein F, Mann C. (2007). The histone chaperone Asf1 at the crossroads of chromatin and DNA checkpoint pathways. Chromosoma. 116, 79-93.
Agez M, Chen J, Guerois R, van Heijenoort C, Thuret JY, Mann C, Ochsenbein F. (2007). Structure of the histone chaperone asf1 bound to the histone h3 C-terminal helix and functional insights Structure Structure. 15, 191-199.
Oliva-Trastoy M, Berthonaud V, Chevalier A, Ducrot C, Marsolier-Kergoat MC, Mann C, Leteurtre F. (2007). The Wip1 phosphatase (PPM1D) antagonizes activation of the Chk2 tumour suppressor kinase. Oncogene. 26, 1449-1458.
Kisseleva-Romanova E, Lopreiato R, Baudin-Baillieu A, Rousselle JC, Ilan L, Hofmann K, Namane A, Mann C, Libri D. (2006) Yeast homolog of a cancer-testis antigen defines a new transcription complex. EMBO J. 9, 3576-85.
Dubacq C, Chevalier A, Courbeyrette R, Petat C, Gidrol X, Mann C. (2006). Role of the iron mobilization and oxidative stress regulons in the genomic response of yeast to hydroxyurea. Mol Genet Genomics. 275, 114-124.
Thuret JY, Blondel M. (2006). Ready for an orange revolution in biotechnology? Biotechnol J. 1, 237-238.
Mousson F, Lautrette A, Thuret JY, Agez M, Courbeyrette R, Amigues B, Becker E, Neumann JM, Guerois R, Mann C, Ochsenbein F. (2005). Structural basis for the interaction of Asf1 with histone H3 and its functional implications Proc Natl Acad Sci U S A. 102, 5975-5980.
Mousson F, Couprie J, Thuret JY, Neumann JM, Mann C, Ochsenbein F. (2004). 1H, 13C and 15N resonance assignments of the conserved core of hAsf1 A. J Biomol NMR. 29, 413-414.
Dubacq C, Chevalier A, Mann C. (2004). The protein kinase snf1 is required for tolerance to the ribonucleotide reductase inhibitor hydroxyurea Mol Cell Biol. 24, 2560-2572.
Badin-Larcon AC, Boscheron C, Soleilhac JM, Piel M, Mann C, Denarier E, Fourest-Lieuvin A, Lafanechere L, Bornens M, Job D. (2004). Suppression of nuclear oscillations in Saccharomyces cerevisiae expressing Glu tubulin. Proc Natl Acad Sci U S A. 101, 5577-5582.
Le Masson I, Yu DY, Jensen K, Chevalier A, Courbeyrette R, Boulard Y, Smith MM, Mann C. (2003). Yaf9, a novel NuA4 histone acetyltransferase subunit, is required for the cellular response to spindle stress in yeast. Mol Cell Biol. 23, 6086-6102.
Le Masson I, Saveanu C, Chevalier A, Namane A, Gobin R, Fromont-Racine M, Jacquier A, Mann C. (2002). Spc24 interacts with Mps2 and is required for chromosome segregation, but is not implicated in spindle pole body duplication. Mol Microbiol. 43, 1431-1443.
Dubacq C, Guerois R, Courbeyrette R, Kitagawa K, Mann C. (2002). Sgt1p contributes to cyclic AMP pathway activity and physically interacts with theadenylyl cyclase Cyr1p/Cdc35p in budding yeast. Eukaryot Cell. 1, 568-582.
Miled C, Mann C, Faye G. (2001). Xbp1-mediated repression of CLB gene expression contributes to the modification of yeast cell morphology and cell cycle seen during nitrogen-limited growth. Mol Cell Biol. 21, 3714-3724.
Leroy C, Mann C, Marsolier MC. (2001). Silent repair accounts for cell cycle specificity in the signalling of oxidative DNA lesions. EMBO J. 20, 2896-2906.
Hermand D, Westerling T, Pihlak A, Thuret JY, Vallenius T, Tiainen M, Vandenhaute J, Cottarel G, Mann C, Mäkelä TP. (2001). Specificity of Cdk activation in vivo by the two Caks Mcs6 and Csk1 in fission yeast EMBO J. 20, 82-90.
Ceccarelli E, Mann C. (2001). A Cdc28 mutant uncouples G1 cyclin phosphorylation and ubiquitination from G1 cyclin proteolysis. J Biol Chem. 276, 41725-41732.
Marsolier MC, Roussel P, Leroy C, Mann C. (2000). Involvement of the PP2C-like phosphatase Ptc2p in the DNA checkpoint pathways of Saccharomyces cerevisiae. Genetics. 154, 1523-1532.
Marcand S, Brevet V, Mann C, Gilson E. (2000). Cell cycle restriction of telomere elongation Curr Biol. 10, 487-490.
Bouquin N, Barral Y, Courbeyrette R, Blondel M, Snyder M, Mann C. (2000). Regulation of cytokinesis by the Elm1 protein kinase in Saccharomyces cerevisiae. J Cell Sci. 113, 1435-1445.
Muñoz-Centeno MC, McBratney S, Monterrosa A, Byers B, Mann C, Winey M. (1999). Saccharomyces cerevisiae MPS2 encodes a membrane protein localized at the spindle pole body and the nuclear envelope. Mol Biol Cell. 10, 2393-2406
Thuret JY, Mann C. (1998). In vivo veritas. Med Sci. 14, 215-218.