1 Groupe Cycle Cellulaire, UMR 6061 Génétique et
Développement, CNRS, 250 Université de Rennes I, IFR 97
Génomique Fonctionnelle et Santé, Faculté de
Médecine, 2 avenue du Pr. Léon Bernard, CS 34317, 35043 Rennes
Cedex, France
2 Laboratoire de Biologie Moléculaire et Cellulaire de la
Différenciation, INSERM U 309, Institut Albert Bonniot, Domaine de la
Merci, 38706 La Tronche Cedex, France
* Author for correspondence (e-mail: claude.prigent{at}univ-rennes1.fr)
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Summary |
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Key words: Chromatin, Histone H3, Serine 10, Phosphorylation, Mitosis
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Introduction |
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The organization of DNA into nucleosomes reduces its length about sixfold.
Each nucleosome is linked to its neighbours by a segment of linker DNA, with
which a distinct `linker histone' interacts. This results in the packaging of
chromatin into 30 nm fibers (van Holde,
1988). Further folding of these fibers generates higher-order
chromatin structures (Woodcock and
Dimitrov, 2001
; Ridgway and
Almouzni, 2001
). DNA is most compact in mitotic chromosomes, and
this requires additional proteins, such as the SMC (structural
maintenance of chromosomes) proteins.
Such compaction gives a highly protected DNA molecule and makes it difficult for regulatory proteins to bind to DNA. Regulatory proteins that locally regulate DNA compaction by interacting with histones therefore control the accessibility of DNA sequences. It has long been thought that post-translational modification of histone tails controls the different levels of DNA organisation. Indeed, they can be acetylated, methylated, ADP-ribosylated, ubiquitylated and phosphorylated on several residues. Additionally, post-translational modification of one residue influences modification of the neighbouring residue.
The four tails provided by the conventional core histones are supplemented
by new tails brought in by histone-variants such as CENP-A, which replaces H3
in the centromeric nucleosomes (Choo,
2001). Given the number of chromosomes per cell, the number of
nucleosomes per chromosome, the number of different histone tails, and the
number of different modifications, the potential complexity of regulation is
immense. Strahl and Allis have therefore proposed the histone code hypothesis
(Strahl and Allis, 2000
),
according to which each combination of post-translational modifications on a
histone tail has a specific function
(Jenuwein and Allis,
2001
).
Histone phosphorylation was first observed in the sixties
(Gutierrez and Hnilica, 1967),
and the kinase responsible was shown to be an AMP-dependent kinase
(Langan, 1968
). Shoemaker and
Chalkley subsequently reported that histone H3 is phosphorylated in vivo
during metaphase at a single tryptic peptide by a cAMP-independent protein
kinase (Shoemaker and Chalkley,
1978
). Taylor then identified the first kinase able to
phosphorylate H3 in vitro at Ser10 as cAMP-dependent kinase
(Taylor, 1982
). Since that
time, an increasing number of protein kinases have been reported as true in
vivo histone H3 Ser10 kinases, including PKA
(DeManno et al., 1999
;
Schmitt et al., 2002
). These
kinases can be divided into kinases that function in signal transduction and
mitotic kinases, which indicates that Ser10 phosphorylation might have
different functions (Cheung et al.,
2000a
; Descamps and Prigent,
2001
).
What are these functions? Here, we discuss two different approaches used to
address this question: the elimination of a putative kinase
(De Souza et al., 2000;
Giet and Glover, 2001
;
Hsu et al., 2000
;
MacCallum et al., 2002
;
Murnion et al., 2001
;
Petersen et al., 2001
;
Scrittori et al., 2001
) and
replacement of histone H3 Ser10 in vivo by non-phosphorylable residue
(Hsu et al., 2000
;
Wei et al., 1999
). We pay
particular attention to the kinases involved and go on to discuss the
different hypotheses that have been proposed to explain Ser10
phosphorylation.
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Phosphorylation of H3 Ser10 in interphase |
---|
|
At interphase, in contrast to at mitosis and meiosis (see below), the
phosphorylation of histone H3 does not affect the whole genome but only a
subset of genes. Ser10 phosphorylation correlates with transcriptional
activation of these genes. For instance, cellular differentiation induced by
follicular stimulating hormone (FSH) is accompanied by an increase in H3
phosphorylation on Ser10 and activation of PKA, which has been proposed to be
the basis for PKA-dependent gene transcription in granulosa cells
(DeManno et al., 1999).
Similarly, Ser10 phosphorylation within the Fos gene occurs during
activation of transcription by mitogens. Both the Rsk2 (ribosomal S6 kinase 2)
(Sassone-Corsi et al., 1999
)
and Msk1 (mitogen- and stress-activated kinase 1)
(Thomson et al., 1999
) kinases
are involved. Histone H3 is also phosphorylated in vivo at
NF-
B-regulated promoters (such as I
B
promoter) during
inflammatory responses triggered by cytokines
(Saccani et al., 2002
). The
kinase involved has recently been identified as I
B kinase
(IKK
), a new Ser10 H3 kinase
(Yamamoto et al., 2003
).
The use of kinases inhibitors such as H89 for Msk1
(Thomson et al., 1999),
PD98059 for MEK1 (MAP kinase kinase)
(Zhong et al., 2000
) or
Sb202190 for p38 MAP kinase (Zhong et al.,
2000
) indicated that kinases from MAP kinase pathways are
responsible for phosphorylation of H3 in interphase - the kinase used
depending on the stimulus or stress.
Another immediate early gene, Jun, is also induced concomitantly
with local Ser10 phosphorylation. Local phosphorylation of H3 at
MAP-kinase-activated genes is associated with acetylation of the same tail
(Clayton et al., 2000),
indicating strong cooperation between both post-translational modifications in
this particular situation. But this is not always so obvious; in the case of
the retinoic acid receptor ß2 (RARß2) promoter, for instance, both
histone H3 and H4 are constitutively acetylated. In the presence of ligand,
rapid Ser10 phosphorylation occurs at the RARß2 promoter but not at
promoters of other genes, which indicates that it is the induction of
phosphorylation that triggers gene activation
(Lefebvre et al., 2002
).
Under heat shock, acetylation of Drosophila polytene chromosomes
remains unchanged whereas global phosphorylation of H3 decreases. This might
seem contradictory but examination of heat shock loci reveals a local increase
in H3 phosphorylation that depends on heat shock transcription factors
(Nowak and Corces, 2000).
Evidence from a variety of systems thus seems to support the idea that Ser10
phosphorylation at interphase is associated with activation of
transcription.
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Phosphorylation of histone H3 at Ser10 during mitosis |
---|
|
Van Hooser et al. have also examined whether cells can enter mitosis
without phosphorylated Ser10 (Van Hooser
et al., 1998) by microinjecting Ser10-sequence-carrying peptides
into S-phase cells to saturate the kinase that phosphorylates Ser10 during the
G2/M transition: the cells arrested in late G2 phase
(Van Hooser et al., 1998
).
This does not directly demonstrate that phosphorylation of Ser10 is necessary
for the G2/M transition but strongly suggests that the kinase is. Analogous
experiments using similar competitive peptides during in vitro condensation of
mitotic chromosomes in Xenopus egg extracts produced data in
agreement with those of Van Hooser et al.
(de la Barre et al., 2000
;
Van Hooser et al., 1998
).
Some genetic experiments in Tetrahymena thermophila have produced
data that are in agreement with those described above
(Wei et al., 1999). A
tetrahymena mutant strain in which Ser10 of histone H3 is replaced by
an alanine residue exhibits altered chromosome condensation. In addition,
abnormal chromosome segregation was observed in this strain, which the authors
hypothesize is associated with the perturbation of chromosome
condensation.
Other genetic data, however, suggest that histone H3 phosphorylation is not
required for chromosome condensation. Yeast mutants lacking Ser10 (Ser10Ala)
show generation times and cell cycle progression identical to those of the
wild-type strain (Hsu et al.,
2000). Thus, in S. cerevisae, a relationship between
phosphorylation at Ser10 of histone H3 and chromosome dynamics has not been
observed. Condensation of mitotic chromosomes induced by incubation of
demembranated sperm nuclei in Xenopus egg extract is, as in cell
culture, accompanied by a phosphorylation of histone H3. During this process a
very fast decondensation (
10 minutes) is followed by a relatively long
(2-3 hours) condensation step. The phosphorylation of histone H3 is complete,
however, during decondensation, and thus chromosome condensation and histone
H3 phosphorylation are uncoupled in this system.
Competition experiments using reconstituted chimeric nucleosomes have shown
that the N-termini of the core histones are essential for mitotic chromosome
compaction (de la Barre et al.,
2001). Crucially, these experiments have demonstrated that the
N-terminus of histone H2B, but not that of histone H3 or its phosphorylation,
is required for chromosome condensation in Xenopus egg extracts
(de la Barre et al., 2001
). In
addition, chromosomes condense properly but do not exhibit phosphorylated H3
in Xenopus extracts depleted of the kinase aurora B
(MacCallum et al., 2002
).
These data argue against a role for histone H3 phosphorylation in chromosome
condensation and are further supported by in vivo experiments in
Drosophila, which reveal a very weak correlation between the level of
histone H3 phosphorylation and the degree of chromosome compaction
(Adams et al., 2001b
). The role
of this modification at mitosis is thus more controversial than that in
interphase.
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Phosphorylation of histone H3 at Ser10 during meiosis |
---|
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The mitotic H3 Ser10 kinase |
---|
Because of the subcellular localisations of the kinases, aurora B makes a
better Ser10 kinase than does aurora A. Aurora A is mainly a centrosomal
protein (Gopalan et al., 1997)
whereas aurora B is a passenger protein - it first localises at chromosome
kinetochores from G2 phase to metaphase and then at the midbody from anaphase
to telophase (Terada et al.,
1998
). Experiments depleting aurora B from Xenopus laevis
egg extracts support the importance of aurora B. It is tightly associated with
INCENP (INner CENtromeric Protein) and survivin, and depletion of the two
produces a reduction in Ser10 phosphorylation
(Adams et al., 2000
;
Bolton et al., 2002
).
Interestingly, chromosome condensation and condensin recruitment remain normal
in the aurora-B- and INCENP-depletion experiments
(Adams et al., 2001b
). Only the
association of XCAP-F (Xenopus chromosome associated protein F) with
condensed chromosomes was affected
(MacCallum et al., 2002
).
Chromosome condensation occurs normally in XCAP-F-depleted Xenopus
egg extract, whereas nucleosome spacing is affected. These data suggest that
phosphorylation of H3 is not directly involved in chromosome condensation but
rather indirectly in complex and subtle mechanisms of chromosome
remodelling.
After aurora B depletion, MacCallum et al.
(MacCallum et al., 2002)
observed a residual Ser10 phosphorylation that they attributed to an
additional protein kinase. Indeed, De Souza et al. have reported that another
protein kinase is responsible for Ser10 phosphorylation in Aspergillus
nidulans, the kinase NIMA (never in mitosis)
(De Souza et al., 2000
). NIMA,
like many other kinases, can phosphorylate Ser10 in vitro
(De Souza et al., 2000
).
Because phosphorylation of Ser10 was thought to be involved in chromosome
condensation, NIMA became a good candidate for several reasons. It triggers
chromosome condensation in cells arrested in S phase
(Ye et al., 1995
;
Osmani et al., 1988
), which is
accompanied by phosphorylation of Ser10
(De Souza et al., 2000
). There
is also a strong correlation between the localisation of NIMA and the
appearance of the phosphoSer10 epitope (De
Souza et al., 2000
). Cells cannot enter mitosis without NIMA,
which implies that mitotic phosphorylation of Ser10 cannot occur. Mammalian
cells possess several NIMA-related kinases (Neks) but apparently only one
functional ortholog of NIMA, Nercc1 kinase
(Roig et al., 2002
). Nercc1
phosphorylates H3 exclusively on serine and threonine residues but whether it
is indeed a Ser10 kinase remains to be shown.
![]() |
The mitotic H3 Ser10 phosphatase |
---|
In vertebrates, both aurora B and PP1 are associated with mitotic
chromosomes (Murnion et al.,
2001). Not only does PP1 dephosphorylate Ser10 as suggested in
C. elegans and S. cerevisiae, but it also dephosphorylates
and inactivates aurora B itself (Murnion
et al., 2001
). This is also true for aurora A
(Tsai et al., 2003
;
Eyers et al., 2003
). This adds
a level of complexity, because elimination of PP1 might thus have two
cumulative effects: constitutive phosphorylation of Ser10 (which cannot be
dephosphorylated) and generation of constitutively active aurora B (which
keeps phosphorylating Ser10) (Fig.
3A) (Murnion et al.,
2001
). The same is true of another aurora B substrate in C.
elegans, REC-8. RNAi knockdown of Glc7
and Glc7ß alters the
localisation of both aurora B and REC-8
(Rogers et al., 2002
). Aurora
B is also activated by okadaic acid, a PP1/PP2A inhibitor, which indicates
that the kinase should interact with the phosphatase, although direct
interactions have not been reported yet
(Sugiyama et al., 2002
).
Aurora A directly binds to PP1 through two domains, NB1 (K162) and NB2 (K343)
(Fig. 3B)
(Katayama et al., 2001
), but
aurora B and aurora C each have only one potential PP1-binding sequence. An
alignment of aurora B sequences shows that this sequence is conserved and is
always located after subdomain 1 of the kinase catalytic domain
(Fig. 3C). This suggests that
aurora B, like aurora A, binds directly to PP1, although this remains to be
proven.
|
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Phosphorylation of histone H3 at Ser28 |
---|
|
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Phosphorylation of CENP-A |
---|
|
![]() |
Phosphorylation of H3 at Ser10 during apoptosis |
---|
![]() |
The function of histone H3 phosphorylation in mitosis |
---|
This model, however, has several drawbacks. First, upon phosphorylation of
histone H3 the positive charge of its tail will decrease from 14 to 12, and
this is very unlikely to result in disruption of the interaction with linker
DNA (Hans and Dimitrov, 2001).
Indeed, numerous reports have shown that hyperacetylation of histone tails,
which reduces the positive charges of the tails from by far more than two,
does not prevent the tails from interacting with nucleosomal DNA
(Mutskov et al., 1998
) and
does not result in chromatin decondensation
(McGhee et al., 1983
;
Dimitrov et al., 1986
). Some
small decondensation effects associated with histone hyperacetylation are only
detectable in H1-depleted chromatin
(Garcia-Ramirez et al.,
1995
).
Second, the model implies that H3 adopts an -helical conformation
upon binding to DNA, which is stabilized upon phosphorylation of Ser10. No
firm data, however, have demonstrated that this is really the case. Third, the
decreased efficiency of UV crosslinking of histone H3 to DNA could reflect a
slightly modified mode of binding of the H3 tail to linker DNA. It should be
noted that the UV laser crosslinking depends on both the close contact of the
amino acid residues with the bases and their proper spatial orientation
relative to each other (for a review, see
Pashev et al., 1991
). Hence, a
slightly modified binding of the tail H3 to the linker DNA could not allow a
proper orientation of the H3 tail residues relative to the nucleobases, which
would result in smaller crosslinking efficiency. Finally, no unambiguous data
have shown that higher amounts of endogenous polyamines bind to mitotic
chromosomes compared with those bound to interphase chromatin.
A second model is based on the idea that the condensation factors are
recruited to the chromosomes through direct interactions with phosphorylated
histone H3 tail or, in general, with chromatin containing phosphorylated
histone H3 (Wei et al., 1999;
Cheung et al., 2000a
). Thus,
phosphorylation of histone H3 would be viewed as a trigger for chromosome
condensation. The model is not, however, in agreement with the available data,
since the two factors known to be involved in chromosome condensation,
topoisomerase II and the SMC proteins, bind with identical, very low affinity
to both native and tailless nucleosomes
(de la Barre et al., 2000
;
Kimura and Hirano, 2000
).
Another condensation factor, different from topoisomerase II and the SMC
proteins, might bind preferentially to H3 phosphorylated chromatin. This does
not seem to be the case, since chromosomes can be efficiently assembled
without histone H3 phosphorylation
(MacCallum et al., 2002
).
The two main models proposed in the literature are not in good agreement
with the experimental data. Thus, what is the function of histone H3 Ser10
phosphorylation during mitosis? Presently, it is difficult to answer this
question. However, during cell division in mitosis there are two facts that
have been confirmed: the first fact is that histone H3 is always heavily
phosphorylated on Ser10 on metaphase chromosomes; the second fact is that the
same residue becomes dephosphorylated as soon as cells exit mitosis.
Phosphorylation of Ser10 might thus be used to mark chromosomes in such a way
that the cell knows that it is progressing from metaphase to telophase. Hence,
as initially suggested by Hans and Dimitrov
(Hans and Dimitrov, 2001),
histone H3 phosphorylation might be viewed as some type of `ready production
label'. This label must stick to the chromosomes once they have successfully
passed through the different checkpoints and arrived at metaphase. The
presence of such a label is an indication to the cell that the chromosomes are
ready to continue through anaphase. Once the cells have passed through
anaphase, the labelling is not necessary anymore and it is removed.
The `ready production label' hypothesis (Fig. 6) does not imply a relationship between chromosome condensation and histone H3 phosphorylation. It simply implies that once the cell has arrived at metaphase its chromosomes should be phosphorylated, and this is independent of their state of condensation. This explains two `paradoxical' phenomena that cannot be explained by the two other models discussed above: the correlation of chromosome assembly in Xenopus egg extract with sperm decondensation and the heavy phosphorylation of decondensed human chromosomes (obtained upon cell incubation in hypotonic solution) upon their release into the culture medium.
|
The `ready production label' model predicts that processes taking place
after metaphase are associated with histone H3 phosphorylation. This
prediction is in agreement with the available data for the
Tetrahymena strain containing nonphosphorylatable histone H3
(Wei et al., 1999). Indeed,
these strains exhibit abnormal segregation and chromosome loss
(Wei et al., 1999
). It should
be noted, however, that histone H3 phosphorylation may not play an essential
role in some organisms. For example, no causal relationship between
phosphorylation of Ser10 of histone H3 and chromosome dynamics was observed in
S. cerevisiae (Hsu et al.,
2000
). Neither the mitotic mechanism that identifies
phosphorylated Ser10 nor the nature of the information given to the cell by
phosphorylated Ser10 is known.
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Acknowledgments |
---|
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