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Wang et al. Genotoxic NF-kB activation in cancer

However, how DNA damage activates alternative SENP2-dependent inhibition of NF-kB
NF-kB pathway, and the mechanistic roles of IKKα, activation by DNA damage
NEMO or ATM in this genotoxic signaling cascade, In DNA damage signaling, SUMOylation of NEMO
still remain to be elucidated. is a critical signaling event in mediating IKK and NF-
kB activation. SUMOylation is the posttranslational
[58]
RESOLUTION OF DNA DAMAGE-INDUCED modification of lysine residues in target proteins
NF-kB ACTIVATION by covalent connection of a SUMO moiety, and
is biochemically analogous to, but functionally
As NF-kB activation plays critical roles in both distinct from, ubiquitination. Like DUBs restricting
physiological (e.g. immunity, cell proliferation and ubiquitination, individuals from the Sentrin/SUMO-
survival) and pathological (e.g. inflammation, auto- specific protease (SENP) family remove SUMO
immune response and cancer progression) processes, conjugates from their substrates. [98,99] Due to the
tight control of NF-kB activation is essential for reversible nature of SUMOylation, it has been tempting
maintaining homeostasis of cell functions. Negative to speculate that desumoylation by an inducible SENP
feedback regulation assumes an important part in may negatively regulate genotoxic NF-kB activation.
the control of NF-kB activity. [89,90] A classic example Indeed, it was found the SENP2 and SENP1 are major
is NF-kB-dependent induction of IkBα synthesis after and minor negative regulators, respectively, of NF-kB
stimulation, which specifically antagonizes NF-kB signaling induced by genotoxic stimuli. [100] Among the
activity and prevents prolonged NF-kB activation. [91,92] six human SENPs, SENP2 interacted most efficiently
Cells deficient in IkBα present basal, and more with NEMO and robustly attenuated NF-kB activation
sustained signal-inducible, NF-kB activities. [93] by genotoxic stress. SENP2 overexpression decreased
the level of NEMO SUMOylation and NF-kB activation
Another shared negative feedback mechanism relies initiated by DNA damage. While wild-type MEFs
on an induced inhibitory mechanism targeting NF- demonstrated transient NF-kB activation, Senp2 −/−
kB-activating signaling events. Recent studies have MEFs indicated increased genotoxic stress-instigated
shown that expression of deubiquitinases (DUBs), NEMO SUMOylation and NF-kB activation. [100] More
such as A20, are prompted by TNFα stimulation in an interestingly, SENP2 and SENP1 genes are direct targets
NF-kB-dependent manner. These DUBs then cleave of NF-kB whose transcription was substantial increased
polyubiquitin chains to limit IKK activation. [94-97] Thus, upon DNA damage. Chromatin IP analysis indicated
a deficiency in DUBs A20 or CYLD (cylindromatosis) that treatment with the genotoxic drug etoposide, but
can prompt augmented and sustained NF-kB activity not TNFα, leads to increased H3K4me2 at the SENP2
in response to inflammatory stimuli and lead to promoter, an epigenetic marker associated with active
inflammatory disorders as well as oncogenesis. In the transcription. [101,102] The induced histone methylation
following section, we focus on the negative feedback was ATM-dependent, which is consistent with previous
mechanisms induced by DNA damage, which limit the findings that ATM regulates telomere elongation
genotoxic NF-kB activation [Figure 2]. through the H3K4 methyltransferase SpSet1p. [103]

Figure 2: Negative feedback mechanisms modulating genotoxic NF-kB activation. Upon genotoxic NF-kB activation, desumoylation
enzyme SENP2 can be transcriptionally upregulated, which in turn decreases NEMO sumoylation and suppresses genotoxic NF-kB
signaling. Similarly, MCPIP1 can be upregulated by NF-kB in response to genotoxic treatment. MCPIP1 may decrease NEMO linear
ubiquitination and ELKS K63 polyubiquitination by facilitating their interaction with USP10. Meanwhile, MCPIP1/USP10 forms a complex
with TANK, which bridges the association of the deubiquitinase complex with TRAF6 and suppresses TRAF6 ubiquitination. All these
deubiquitination events could contribute to the abrogation of genotoxic NF-kB activation. In addition, as a canonical NF-kB target gene,
IkBα induction could also diminish NF-kB activation by DNA damage. NF-kB: nuclear factor kappa B; SENP2: Sentrin/SUMO-specific
protease 2; MCPIP1: monocyte chemotactic protein-1-induced protein-1; TANK: TRAF family member-associated NF-kB activator; TRAF6:
TNF receptor-associated factor 6
Journal of Cancer Metastasis and Treatment ¦ Volume 3 ¦ March 27, 2017 51