binds tightest to H3K4me3 and H3K4me2, but it also recognizes H3K4me1 with
relatively high affinity and even H3K4me0 for the human protein (K D s ~0.5 μM,
~1 μM, ~4 μM, and 24 μM, respectively) [57].
Sawadee homeodomain homolog 1 (SHH1) from Arabidopsis thaliana is a
protein involved in the RNA-directed DNA methylation (RdDM) pathway [125].
This pathway involves plant-specific RNA polymerases such as Pol-IV, which
initiates the synthesis of siRNAs [126]. SHH1 enables the production of siRNAs
from a large number of RdDM targets and is required for Pol-IV to occupy the
corresponding loci. SHH1 includes tandem Tudor domains (SHH1-TT), also called
Sawadee domain. SHH1-TT, which binds histone H3 methylated at Lys9, is essential in vivo for Pol-IV to occupy RdDM targets and for the maintenance of siRNA
and DNA methylation levels [127]. SHH1-TT is similar to UHRF1-TT, but with
a unique zinc-binding site in Tudor 2. Extensive structural and binding studies
have shown that SHH1 binds equally well to H3K9me1, H3K9me2, and
H3K9me3 peptides with K D s of ~2 μM.
The multidomain ubiquitin ligase UHRF1 (ubiquitin-like, PHD, and ring fingercontaining 1) is required for the maintenance of DNA methylation patterns
by DNMT1 (DNA methyltransferase 1) at hemimethylated CpG dinucleotides
[128, 129]. These sites are recognized by UHRF1 SRA (SET- and RING-associated
domain) domain, which also directly binds DNMT1 [130–132]. In addition, UHRF1
associates with H3K9me3 and H3K4me0 or H3K4me1 [133]. UHRF1 ubiquitylates
histone H3 at lysine 23, and this mark is required for the recruitment of DNMT1
to DNA replication sites [134]. Therefore, UHRF1 links two layers of epigenetic
information: the methylation of DNA associated with transcriptional silencing
and histone methylation marks associated with chromatin condensation and inhibition of gene expression [135]. The tandem Tudor domains of UHRF1 (UHRF1-TT)
binds H3K4me0K9me3 with a K D of ~20 μM. Noteworthy, the affinity for
H3K4AK9me3 or H3K4me3K9me3 is significantly lower (K D s ~210 μM and
~90 μM, respectively) [133]. More recently, it was shown that the PHD finger
at the C-terminus of UHRF1 is also involved in recognition of methylated histone
H3 [130, 136, 137].
A particular example of TT-containing protein is Spindlin-1, a transcriptional
coactivator that has been reported to regulate the expression of rRNA genes, which
are regulated by the MAZ transcription factor and Wnt target genes [138, 139].
The protein is named after the meiotic spindle in mice where it was initially found
[140]. Later, the gene for the human ortholog (SPIN1) was found as overexpressed
in a screen for genes involved in ovarian cancer [141]. Spindlin-1 levels are elevated
in a number of different cancers, including non-small cell lung cancers, ovarian
tumors, and some hepatic carcinomas [138, 142], and the protein displays a diffuse
nuclear localization and is enriched in nucleoli [139]. Spindlin-1-overexpressing
cells undergo a complete morphological change and show increased cell growth as
well as cell cycle delay in metaphase and chromosome instability [143]. It has been
proposed that cancer cell growth promotion by Spindlin-1 occurs via WNT/TCF-4
signaling activation [142].
358
G. Sbardella
relatively high affinity and even H3K4me0 for the human protein (K D s ~0.5 μM,
~1 μM, ~4 μM, and 24 μM, respectively) [57].
Sawadee homeodomain homolog 1 (SHH1) from Arabidopsis thaliana is a
protein involved in the RNA-directed DNA methylation (RdDM) pathway [125].
This pathway involves plant-specific RNA polymerases such as Pol-IV, which
initiates the synthesis of siRNAs [126]. SHH1 enables the production of siRNAs
from a large number of RdDM targets and is required for Pol-IV to occupy the
corresponding loci. SHH1 includes tandem Tudor domains (SHH1-TT), also called
Sawadee domain. SHH1-TT, which binds histone H3 methylated at Lys9, is essential in vivo for Pol-IV to occupy RdDM targets and for the maintenance of siRNA
and DNA methylation levels [127]. SHH1-TT is similar to UHRF1-TT, but with
a unique zinc-binding site in Tudor 2. Extensive structural and binding studies
have shown that SHH1 binds equally well to H3K9me1, H3K9me2, and
H3K9me3 peptides with K D s of ~2 μM.
The multidomain ubiquitin ligase UHRF1 (ubiquitin-like, PHD, and ring fingercontaining 1) is required for the maintenance of DNA methylation patterns
by DNMT1 (DNA methyltransferase 1) at hemimethylated CpG dinucleotides
[128, 129]. These sites are recognized by UHRF1 SRA (SET- and RING-associated
domain) domain, which also directly binds DNMT1 [130–132]. In addition, UHRF1
associates with H3K9me3 and H3K4me0 or H3K4me1 [133]. UHRF1 ubiquitylates
histone H3 at lysine 23, and this mark is required for the recruitment of DNMT1
to DNA replication sites [134]. Therefore, UHRF1 links two layers of epigenetic
information: the methylation of DNA associated with transcriptional silencing
and histone methylation marks associated with chromatin condensation and inhibition of gene expression [135]. The tandem Tudor domains of UHRF1 (UHRF1-TT)
binds H3K4me0K9me3 with a K D of ~20 μM. Noteworthy, the affinity for
H3K4AK9me3 or H3K4me3K9me3 is significantly lower (K D s ~210 μM and
~90 μM, respectively) [133]. More recently, it was shown that the PHD finger
at the C-terminus of UHRF1 is also involved in recognition of methylated histone
H3 [130, 136, 137].
A particular example of TT-containing protein is Spindlin-1, a transcriptional
coactivator that has been reported to regulate the expression of rRNA genes, which
are regulated by the MAZ transcription factor and Wnt target genes [138, 139].
The protein is named after the meiotic spindle in mice where it was initially found
[140]. Later, the gene for the human ortholog (SPIN1) was found as overexpressed
in a screen for genes involved in ovarian cancer [141]. Spindlin-1 levels are elevated
in a number of different cancers, including non-small cell lung cancers, ovarian
tumors, and some hepatic carcinomas [138, 142], and the protein displays a diffuse
nuclear localization and is enriched in nucleoli [139]. Spindlin-1-overexpressing
cells undergo a complete morphological change and show increased cell growth as
well as cell cycle delay in metaphase and chromosome instability [143]. It has been
proposed that cancer cell growth promotion by Spindlin-1 occurs via WNT/TCF-4
signaling activation [142].
358
G. Sbardella