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

tel-00413908, version 1 - 7 Sep 2009
I.4.2 Posttranslational modifications of histones
Conserved structure of a nucleosome can attain a unique identity by chromatin modifications.
The variations in the DNA organization takes place either through histone variants or
posttranslational modifications of the amino-terminal tails of core histones. Histone
modifications were first described in 1960’s (Allfrey et al., 1964). Since then, they have been
an important focus of chromatin research since these covalent modifications of histones can
regulate gene expression either directly or through recruitment of non-histone effector
proteins. Several protein families of histone modifying enzymes and chromatin binding
effector proteins have now been recognized. Since the amino-terminal tails of histones
protrude out of the nucleosome core, they are accessible to modifying enzymes. These
modifications include lysine acetylation, lysine and arginine methylation, serine and threonine
phosphorylation, ADP-ribosylation and ubiquitination (Figre I.12, Khorasanizadeh, 2004;
Kouzarides, 2007). However, these modifications do not affect integrity of the nucleosome
directly, as nucleosome is stabilized by globular regions of the four core histones. “The
histone fold” imposes strong accessibility constraint because of which very few modifications
are found in the globular domain of core histones eg. methylation of lysin 79 of the histone
H3 (H3K79me) ( Freitas et al., 2004).
The covalent modifications leads to alteration in electrostatic charge of the histones further
leading to change in structural properties of histones and alteration in amino-terminal tail
interactions. It is well established that these histone modifications are used as signals by
chromatin modifying proteins however, the electrostatic force produced by these
modifications might not be sufficient to affect the accessibility of nucleosomal DNA (Polach
et al., 2000; Mutskov et al., 1998). Specific proteins are known to bind to the amino-terminal
tail of histones and carryout or influence its modification. Two principal protein motifs that
play major role in interaction between histone modifications and effector proteins are
‘bromodomains’ and ‘chromodomains’, allowing the recognition of acetylated and methylated
residues respectively. For example, protein HP1 (heterochromatin protein 1) binds to amino-
terminal tail of H3 when methylated at lysine 9 residue via its chromodomain.
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