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

tel-00413908, version 1 - 7 Sep 2009
H2A.Z is assembled by SWR1, a member of SWI/SNF family (Krogan et al., 2003; Kobor et
al 2004; Krogan et al., 2004; Mizuguchi et al., 2004) but the exact mechanism is still not
known. Another histone chaperone called Chz1 preferentially deposits H2A.Z-H2B dimer
(Luk et al., 2007). Taken together, the available data suggests that H2A.Z plays important role
in several cellular processes and can affect architecture of chromatin towards both increased
gene expression as well as gene silencing. These distinct and even antagonistic functions are
probably dependent on the particular dynamics of these nucleosomes and their distinct
mechanisms of deposition.
I.4.1.2.2 H2A.X
H2A.X represents about 10-15% of total H2A in most of the mammalian cells. Its sequence is
very similar to the canonical H2A at amino terminal and core regions however, varies
considerably at carboxy-terminal end (West and Bonner, 1983). In humans, the carboxy-
terminal end of H2A.X differs in both length as well as sequence from H2A. It contains 20
amino acids more than H2A and exhibits homology with lower vertebrate species. In
particular, it contains a very conserved tetrapeptide motif (Ser-Gln-acidic-aliphatic) whose
serine (position 139) gets phosphorylated upon introduction of a double strand break
(Marzluff and Pandey, 1988; Rogakou et al., 1998; Li et al., 2005b). In mammals, a second
(S,T)Q motif is present upstream of this region which also gets phosphorylated (position 136)
but to a lesser extent (Rogakou et al., 2000). Furthermore, another upstream conserved region
is formed by GKK cassette and posttranslational modifications of these three residues play
important functional role (Li et al., 2005b).
Redon et al., (2002) demonstrated phosphorylation of H2A.X (γH2A.X) as a general
phenomenon correlated with DNA double strand breaks and suggested its role in DNA repair.
This phosphorylation is carried out by three kinases of PIKK family namely, ATM, DNA-PK
and ATR (Stiff et al., 2004). ATM (ataxia telangiectasia (A-T) mutated protein) is a crucial
kinase for the signal transduction DSB pathway (Savitsky et al., 1995) and is known to play a
dominant role in H2A.X phosphorylation than the other two kinases (Burma et al., 2001;
Fernandez-Capetillo et al., 2002; Redon et al., 2002). The phosphorylation of H2A.X could
either directly open chromatin or can affect histone interactions and thus carryout opening of
30 nm fiber (Li et al., 2005b). For DNA repair chromatin decondensation is a prerequisite.
The phosphorylated serine of γH2A.X is present near the C-terminal end and is accessible for
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