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et al. 2006). These observations may merely represent minor shifts in the availability
of free repressive proteins, but could also signify inactivation by segregation. The
repressors in these domains may also affect the reduction of replicative success.
We do not even know whether PML and IE1 interact directly, except that evidence
from Daxx
-/-
cells seems to exclude Daxx as an adapter (Tang and Maul 2003).
The mechanism, or at least the molecular domains of PML essential for PML-
induced inhibition, can now be investigated by using the PML-depleted cells and
manipulating the individual PML isotype, specifically PML IV. This includes the
manipulation of its ND10-forming capability. Such investigations may determine
whether the HCMV replication sequence is dependent on the ability of PML to
multimerize and separately to form complexes by attracting Daxx, and through
Daxx, ATRX (Ishov et al. 2004).
Daxx
Daxx interacts at its C-terminal end with sumoylated PML (Ishov et al. 2004), and
the SUMO-interacting motif (SIM) at the very end of the molecule is the necessary
domain for interaction with may other repressors. Single amino acid changes in the
I I V L sequence of Daxx abrogate ND10 association and functional repression of
the glucocorticoid receptors (Lin et al. 2006). Daxx therefore likely functions as an
adaptor protein or corepressor. The repressive effects of Daxx on HCMV have been
documented by siRNA suppression of hDaxx (Cantrell and Bresnahan 2005, 2006;
Saffert and Kalejta 2006) and for MCMV, by inference, using mouse Daxx
-/-
cells
(Tang and Maul 2006). The viral counter-defenses seem to center on the tegument
protein pp71, which was identified as the first Daxx-interacting protein. Pp71 and
Daxx interact in the N-terminal half of the Daxx molecule (Ishov et al. 1999, 2002;
Hofmann et al. 2002; Marshall et al. 2002) away from the PML-interacting
C-terminal end (Ishov et al. 1999). pp71 is enriched in all ND10 after infection
(Ishov et al. 2002). We assume the viral genome deposition at ND10 to come about
by interaction of the viral DNA binding to pp71, which in turn is bound to Daxx and
thus deposited at highly increased frequency to the high concentration of PML at
ND10 (Ishov et al. 1999, 2002; Hofmann et al. 2002; Marshall et al. 2002). If Daxx
is a repressor and binds pp71 to produce an inactive transactivator complex, the viral
genome should be suppressed at ND10, a nuclear defense. Here IE1 may counter
this defense by its binding of Daxx. The balance between these separate interactions
should help reveal the choreography of sequential, temporal and spatial interactions
that set the stage for the progress or suppression of the lytic cycle.
Our experiments also show that MCMV IE1 appears to interact with PML or
Daxx independently. Because Daxx interacts with the histone deacetylases (HDAC)
(Li et al. 2000), we tested the possibility that IE1 binds indirectly to HDAC.
Identifying an IE1-HDAC interaction, however, may have been fortuitous, since
HDAC does not normally localize to ND10, but does so in the presence of IE1.
HDAC may be recruited to ND10 by IE1 during the early stages of infection, when
