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Wang et al. Genotoxic NF-kB activation in cancer

region of NEMO and target the same residues. When chains also contribute to NF-kB activation by DNA
[76]
overexpressed, cIAP1 inhibits NEMO SUMOylation. damage. Linear ubiquitin chains are connected by a
Although the function of NEMO monoubiquitination head-to-tail peptide bond between C-terminal Gly76 of
is not fully elucidated, various studies suggested that one ubiquitin and N-terminal α-amino group on Met1
ubiquitination also regulates subcellular localization of of another ubiquitin molecule. The LUBAC protein
[77]
NEMO. In contrast to SUMOylation, monoubiquitination complex comprised of hemeoxidized IRP2 ubiquitin
appears to promote nuclear export of NEMO so as to ligase-1 (HOIL1), HOIL1-interacting protein (HOIP) and
transduce a nuclear signaling into cytoplasm and relay shank-associated RH domain interactor (SHARPIN),
to downstream signaling events. was identified as the only E3 ligase specifically to
promote linear ubiquitin chain formation. [78-81] Upon
The nuclear export of NEMO is essential to convey TNFα stimulation, LUBAC was found in a TNFR-
the signal from nucleus to cytoplasm and the supercomplex where it facilitates linear ubiquitination
underlying mechanisms have been only partially of RIP1 and NEMO. [82,83] The UBAN domain of NEMO
elucidated. Huang et al. [58,68] demonstrated that NEMO has high affinity for interaction with the linear ubiquitin
monoubiquitination is required for its Ca - and Ran- chain, [84,85] suggesting the linear ubiquitin chains
2+
GTP-dependent nuclear export. ATM and NEMO attached on NEMO or RIP1 may be stabilizing the
are found to be exported together. Another study NEMO/IKK complex within the TNFR-supercomplex,

showed that NEMO may be monoubiquitinated in the leading to effective activation of IKK. Similarly, NEMO
cytoplasm after the export of SUMOylated NEMO could be modified by linear ubiquitin chains in the
from the nucleus. ATM may be also exported cytoplasm of cells exposed to DNA damage. LUBAC
[70]
in a Ca -dependent but PARP-1/NEMO/PIASy- is required for DNA damage-induced NEMO linear
2+
independent manner. Nevertheless, the presence ubiquitination. [76]
of monoubiquitinated NEMO in cytoplasm delivers
the nuclear DNA damage signal to cytoplasmic The linear chain-conjugated lysine residues in NEMO
compartment and leads to a cytoplasmic NEMO: have been identified as Lys285 and Lys309. Lys309
ATM: IKK complex, which further promotes NF-kB could be modified by monoubiquitination and Lys285
activation. [21] was shown to be conjugated with a single ubiquitin
moiety upon DNA damage in another study.
[70]
Cytoplasmic steps: ATM mediates TAK1-IKK Therefore, it is likely the mono-ubiquitin attached
activation on Lys285 and 309 may serve as a cornerstone for
In the cytoplasm, ATM still plays important roles to further extension of linear ubiquitin chains. The K63
activate the IKK complex. NEMO and ATM were found chains attached on ELKS and TRAF6, along with linear
to form a complex with the IKK-associated protein ELKS chains anchored on NEMO, may form an intertwined
(a protein rich in glutamate, leucine, lysine and serine, network which provides an optimal binding platform for
also called ERC1). ELKS has been shown to play recruiting and stabilizing association of TAK1/TAB1/
[68]
a role in synaptic plasticity, intracellular transport, and TAB2 and IKK complexes. The clustering of TAK1 and
exocytosis by regulating release of neurotransmitters IKK complexes leads to effective auto-phosphorylation
at presynaptic active zones. [71-73] ELKS has been found and activation of TAK1 and subsequent TAK1-
as a putative IKK complex component regulating IKK- dependent IKK activation upon DNA damage. After
dependent IkBα phosphorylation in TNFα-induced IKK activation, the downstream signaling events are
NF-kB activation. ELKS also forms a complex with similar to that in the classical NF-kB signaling cascade,
[74]
NEMO, ATM and IKK, which is required for activation which involves IKK-dependent IkBα phosphorylation
of IKK-upstream kinase TGF-beta activated kinase 1 and degradation, free NF-kB nuclear translocation and
(TAK1). [68,75] Further investigation revealed that ELKS is target gene transcription alteration.
conjugated with K63-linked polyubiquitin chains which
depends on ATM and ubiquitin ligase XIAP. Moreover, In addition to the well-described mechanistic
ATM may also directly bind and promote the ubiquitin connection linking DNA damage signals to the
ligase activity of TNF receptor-associated factor 6 canonical IKK-NF-kB pathway, DNA damage may
(TRAF6), leading to TRAF6 auto-ubiquitination with also lead to activation of alternative NF-kB pathways.
K63-chains. The K63-linked polyubiquitin chains RelB was found to be enriched in the nuclei following
[70]
conjugated on ELKS and TRAF6 could then serve as ionizing radiation in prostate cancer cells, which
a docking platform of TAK1/TAB1/TAB2 complex and correlated with poor prognosis in prostate cancer
lead to its activation. patients. [86-88] In osteosarcoma cell lines, p100
phosphorylation and subsequent processing to p52
Besides K63-linked polyubiquitination, linear ubiquitin observed following multiple forms of DNA damage.
50 Journal of Cancer Metastasis and Treatment ¦ Volume 3 ¦ March 27, 2017