Etudes sur le mécanisme de remodelage des nucléosomes par ...

tel-00413908, version 1 - 7 Sep 2009
upon which most important biological processes like transcription, replication, repair and
recombination takes place. These processes require quick changes in chromatin organization
and structure. In order to make the DNA accessible to enzymatic machinery, the compacted
DNA fiber needs to be unraveled (van Holde and Zlatanova, 1996). Physical parameters such
as the affinity of the DNA sequence to the histone octamer or the intrinsic curvature of the
DNA sequence can have strong effects on the structure of chromatin. Indeed, nucleosomes on
some DNA sequences are more prone to temperature induced octamer repositioning than
sequences which have more affinity towards the octamer (Beard et al., 1978; Meersseman et
al., 1992; Falus et al., 2004; Lowary and Widom, 1998). Moreover, nucleosomes are able to
adapt to strong distortions induced by binding of ligand on the DNA without losing the
contact with the histone octamer (Edayathumangalam and Luger, 2005). Certain transcription
factors such as NF-κB can bind to DNA without inhibition or major modification of the
nucleosome (Angelov et al., 2004). This intrinsic dynamics of the nucleosome (or breathing)
does not allow the complete DNA to be accessible for all the cellular machineries. Moreover
this “breathing” of the nucleosomal DNA is limited to the ends of the nucleosome (Anderson
et al., 2002). Therefore, cells have developed certain mechanisms to ensure modulation of
DNA accessibility. Three principal methods to ensure this plasticity are, as described in the
following sections, incorporation of histone variants, histone covalent modifications and ATP
dependent chromatin remodeling.
I.4.1 Incorporation of Histone variants
The structure of chromatin can be adapted to perform specialized functions by variation in its
core histone composition. Histones deposited at the time of DNA replication are called as
conventional histones (H2A, H2B, H3 and H4). They represent majority of histones (60-90
%) in the cells and are synthesized only during S-phase of cell cycle. However, synthesis of
histones out of this phase of replication also takes place. These are non-allelic counterparts of
conventional histones and are called as ‘variants’. They can be deposited in the nucleosome a
manner independent of the replication and have the capacity to substitute canonical histones
within the nucleosome. Hence, these are also called as ‘replacement histones’. Except H4,
multiple variant forms of all other core histones exist, however, alternative mRNA forms of
H4 also seem to be present (Boulard et al., 2007; Poirier et al., 2006; Gendron et al., 1998).
The percentage identity of each histone with its conventional counterpart is highly variable
(from 48 to 99.9%) (Figure I.9). Some are much conserved and are present throughout the
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