Objectif
Metazoa evolved homogametic and heterogametic sexes. In heterogametic sexes one of the two sex chromosomes underwent loss of essential genes and molecular mechanisms evolved to compensate for this loss.
In fruit flies, males up-regulate the transcription levels of many genes on the only sex chromosome by 2-fold. This effect is associated with acetylation of H4K16 mediated by MOF, the catalytic subunit of the Dosage Compensation Complex (DCC). The DCC can be narrowed down to the MSL1-MSL3-MOF complex (MW=280kDa). MSL1 and MSL3 enhance MOF catalysis, probably by inducing a conformational change in the enzyme, and guide its substrate recognition, by an unknown mechanism. To answer these questions I propose to solve the three-dimensional structure of the MOF-MSL1-MSL3 complex and compare it to the structure of MOF alone. Moreover, I propose to elucidate the three-dimensional structure of the MSL1-MSL3-MOF/nucleosomes complex (MW=400kDa) using a combination of X-ray crystallography and electron microscopy.
MOF belongs to the family of MYST acetyl-transferases involved in many nuclear processes such as DNA damage response and transcription. The structure of MSL1-MSL3-MOF bound to nucleosomes will reveal how MYST enzymes function.
More in general, the DCC can be regarded as a powerful molecular tool to understand how chromatin-remodelling complexes recognize nucleosomes and modify them.
Champ scientifique
- natural sciencesearth and related environmental sciencesgeologymineralogycrystallography
- natural sciencesphysical sciencesopticsmicroscopyelectron microscopy
- natural scienceschemical sciencescatalysis
- natural sciencesbiological sciencesgeneticschromosomes
- natural sciencesbiological sciencesbiochemistrybiomoleculesproteinsenzymes
Thème(s)
Appel à propositions
FP7-PEOPLE-2009-IEF
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Régime de financement
MC-IEF - Intra-European Fellowships (IEF)Coordinateur
W1B 1AL LONDON
Royaume-Uni