Biology Reference
In-Depth Information
IE1 accumulates at ND10. The IE1-dependent segregation of HDAC to ND10 may
not be significant, because there is little segregated, relative to the amount present
in the nucleus. On the other hand, the large amounts of IE1 expressed, especially
after ND10 dispersal, may be more significant, because IE1 might flood the nucleus
sufficiently to reduce free HDAC, relieving the HDAC-associated suppression of
chromatinized viral genomes. This is consistent with results from HDAC activity
assays, which show that IE1 binding to HDAC inhibits HDAC deacetylation (Tang
and Maul 2003). IE1, therefore, may not exert its primary effects at sites where it
is most concentrated; rather, it appears that IE1 functions throughout the nucleus as
an HDAC scavenger (at least HDAC 1 and 2 or their complexes), and possibly, as
a scavenger for other host proteins.
ATRX
ATRX (alpha thalassemia-mental retardation, X linked) protein has not yet been
associated with CMV biology. However, ATRX was the first cellular protein found
to interact with Daxx at an N-terminal region and localize to ND10 by the adapter
function of Daxx (Ishov et al. 2004). ATRX is a member of the SWI/SNF family
of helicases or ATPases with chromatin remodeling activity, and it associates with
HP1 (Picketts et al. 1996, 1998; Gibbons et al. 1997) and with the SET domain of
chromatin modifying proteins (Cardoso et al. 1998). ATRX and Daxx are only
removed from ND10 for a short time during the S/G2 interphase, suggesting rees-
tablishment of the epigenetic properties of newly replicated heterochromatin
(Ishov et al. 2004). Conditional genetic ablation of ATRX in mice has similar
effects on developing brain structures, as has congenital HCMV infection (Berube
et al. 2005). It is tempting to speculate that Daxx/ATRX is removed by IE1 during
stochastic reactivation events of latent HCMV in the developing embryo. If so,
HCMV silencing and development of latency during congenital infection may not
be a totally benign cellular defense. We are now investigating the possibility that
permissive cells can silence competent virus, and anticipate that ATRX is involved
in the suppression of CMV genomes.
Sp100
Sp100 is a constitutive ND10-associated protein that has been shown to affect
HSV1 immediate early protein expression by affecting the promoter of these
proteins (Taylor et al. 2000; Wilcox et al. 2005; Isaac et al. 2006; Negorev et al.
2006). Sp100A, the dominant isotype found at ND10, produces a mild activation.
All other isoforms that have apparent DNA- or chromatin-binding domains
(Sp100B-SAND domain; Sp100C-PhD and Bromo domain; Sp100HMG-HMG
domain) are repressive, with the Sp100B having the strongest effect. Preliminary
