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International Journal of Molecular Medical Science
2
stability, G0/G1 and G1/S transition in cell cycle, and
lineage commitment /specification of hematopoietic
stem cells. IK also exhibits a tumor suppressor function in
lymphocyte precursors, which has been attributed to
its ability to repress expression of oncogenic genes via
chromatin remodeling in association with the
SWI/SNF remodeling complex (Georgopoulos, 2002;
Cobbs et al., 2000; Thompson et al., 2007;
Merkenschlager, 2010) and recruitment of potentially
oncogenic proliferation-promoting genes to
pericentromeric heterochromatin (PC-HC) as well as
the regulatory control of the homing of the
nucleosome-remodelling and histone-diacetylase
(NuRD) complex to lymphoid lineage-specific IK
target genes that are required for orderly
differentiation of
lymphocyte precursors
(Georgopoulos, 2002; Cobbs et al., 2000; Thompson
et al., 2007; Merkenschlager, 2010; Yoshida et al.,
2010; Bottardi et al., 2011; Zhang et al., 2011; Dovat
et al., 2011). Impaired DNA binding activity of IK has
been associated with a release of NuRD from IK
target genes to cause both a maturational arrest in
lymphocyte ontogeny and an “illegitimate” activation
of a network of genes that promote leukemogenesis
(Zhang et al., 2011). Functional deficiency of IK due
to expression of non-DNA binding dominant-negative
IK isoforms caused by aberrant splicing (Sun et al.,
1999) or genomic mutations (Mullighan et al., 2009)
has been detected in leukemic lymphocyte precursors
from patients with acute lymphoblastic leukemia
(ALL), the most common form of childhood cancer.
Currently, our knowledge regarding the upstream
regulators of IK function is relatively limited
(Georgopoulos, 2002; Cobbs et al., 2000; Thompson
et al., 2007; Merkenschlager, 2010). IK function,
stability, and subcellular localization are generally
thought to be regulated by posttranslational
modification and heterodimerization with other
members of the IK family of DNA binding proteins
(Georgopoulos,
2002;
Sun et
al.,
1996).
Phosphorylation of IK by casein kinase II (CK2)
inhibits its many functions and promotes its
degradation via the ubiquitin/proteosome pathway
(Gurel et al., 2008). Conversely, dephosphorylation of
IK by protein phosphatase 1 is critical for its ability to
bind to target DNA sequences, localize to PC-HC in
the nucleus, and exert its regulatory functions
(Popescu et al., 2009). In a recent study, we identified
the spleen tyrosine kinase (SYK) as a posttranslational
regulator of IK and showed that SYK-induced
activating phosphorylation of IK at unique C-terminal
serine phosphorylation sites S358 and S361 is
essential for its nuclear localization and optimal
transcription factor function (Uckun et al., 2012).
Likewise, BTK was identified as a regulator of IK that
phosphorylates IK at unique phosphorylation sites
S214 and S215 in the close vicinity of its ZF4 within
the DNA binding domain, thereby augmenting its
sequence-specific DNA binding activity (Ma et al.,
2013).
Our recent studies revealed a previously unknown
function of the DNA repair protein Ku, which plays an
important role in repair of DNA double-strand breaks
by nonhomologous end joining (NHEJ) (Suzuki et al.,
2010; Walker et al., 2001), as a partner of IK that
physically associates with IK thereby augmenting its
nuclear localization and sequence-specific DNA
binding activity (Ozer et al., 2013). Ku is the only
protein outside the IK family of ZF proteins shown to
non-enzymatically improve the function of IK as a
sequence-specific DNA binding protein via
heterodimerization.
RNA interference (RNAi)
experiments using Ku70-specific or Ku80-specific
small interfering RNA (siRNA) further demonstrated
that Ku regulates the expression levels of validated IK
target genes in a human cell line (Ozer et al., 2013).
The interaction of Ku components with IK likely
contributes to the anti-leukemic effects of IK as a
tumor suppressor, because Ku70 as well as Ku80
haploinsuffiency in mice caused development of a
lymphoproliferative disorder (LPD) involving
CD2
+
CD4
+
CD8
+
CD1
+
IL7R
+
thymic T-cell precursors
with functional IK deficiency (Ozer et al., 2013). It is
noteworthy that comprehensive bioinformatic studies
on haploinsufficiency have indicated that the
Ku80/XRCC5 gene is highly likely to be
haploinsufficient (Huang et al., 2010). As Ku70 and
Ku80 are not haploinsufficient for DNA double strand
break (DSB) repair and even Ku-null cells have
normal DNA repair activity due to hyperactive
Molecular Medical Science, Int’l Journal of