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Wang et al. Genotoxic NF-kB activation in cancer

Moreover, ATM was shown to promote DNA repair feedback response to attenuate NF-kB activation by
by regulating RNF20 phosphorylation and histone DNA damage.
methylation, including H3K4me2. [104,105] These results
also indicate that ATM not only mediates activation of TANK-dependent inhibition of NF-kB signaling
NF-kB signaling in response to DNA damage, it also TRAF family member-associated NF-kB activator
facilitates NF-kB-dependent transcription by promoting (TANK, also known as I-TRAF) was originally identified
epigenetic modification to synergistically enhance NF- as a protein associated with the TRAF2 and TRAF3,
kB-target gene induction. As in the situation with DUBs and involved in TRAF-mediated NF-kB signaling
in the cytokine signaling, [106] the relative significance pathways. [113-115] In response to viral infection-induced
of NF-kB-dependent feedback regulation mediated retinoic acid-inducible gene 1 (RIG-I) activation, TANK
by SENPs in genotoxic signaling probably depends serves as an adaptor bridging TRAF3 association with
on cell types and the nature of DNA damage stimuli. TBK1 and IKKϵ, which promotes phosphorylation and
Nevertheless, SENP2/1 induction upon genotoxic activation of Interferon Regulatory Factor 3 (IRF3)/IRF7
stress provided the first negative-feedback mechanism as well as NF-kB signaling. [116-119] However, TANK was
to uniquely regulate DNA damage-induced NF- also shown to negatively regulate NF-kB activation. [119,120]
kB activation through modulating SUMOylation/ NF-kB activation upon TLR or BCR (B-cell receptor)
desumoylation of NEMO. stimulation was enhanced in macrophages and B
cells isolated from Tank−/− mice compared with their
Suppression of genotoxic NF-kB activation by wild-type counterparts. Interestingly, TANK deficiency
MCPIP1/USP10 increased TRAF6 ubiquitination in response to TLR
Monocyte chemotactic protein-1-induced protein-1 stimulation in macrophages, which may account
(MCPIP1, also called ZC3H12A) was initially recognized for the increased NF-kB activation. However, no
as a potential transcription factor in cardiac myocytes canonical deubiquitination enzyme domain can be
regulating apoptosis and chronic inflammatory found in TANK. Also, neither A20 nor CYLD, two
response. [107] Further studies demonstrated that common DUBs involved in negative regulation of NF-
MCPIP1 can be induced in macrophages, which kB signaling, was found as TANK-binding partners. [119]
depend on down-regulation of NF-kB signaling, to Therefore, the mechanism by which TANK inhibited
modulate inflammatory gene expression. MCPIP1- TRAF6 ubiquitination has been elusive.
knockout mice displayed severe immune disorders,
growth retardation and premature death. [108-110] It was We recently reported that TANK represses genotoxic
found that MCPIP1 could bind to the 3’-untranslated NF-kB activation, which may rely on suppression of
regions (UTRs) of a subset of inflammatory cytokine TRAF6 ubiquitination. [121] TRAF6 polyubiquitination
genes including IL6 and IL12, and destabilize has been shown to play an important role in mediating
[70]
the bound mRNAs through its RNase activity. [110] IKK activation upon DNA damage. DNA damage-
Intriguingly, MCPIP1 was found to limit LPS-induced induced NF-kB activation and TRAF6 ubiquitination
NF-kB activation in macrophages through expulsion were substantially increased in TANK-deficient cells
of polyubiquitin chains from TRAF proteins. [109,111] The which was reduced by reconstitution of TANK. TRAF6
transcription of MCPIP1 was also upregulated, in a NF- was found to interact with TANK through its TRAF-C
kB-dependent fashion, in cells exposed to genotoxic domain and this interaction is required for TANK-
stimulation. [112] Further investigation revealed that mediated deubiquitination of TRAF6. Intriguingly,
MCPIP1, although itself lacks DUB activity, could TANK was identified as a MCPIP1-interacting protein
serve as an adaptor protein to enhance interaction of in a proteomic screen and we confirmed that TANK
deubiquitinase USP10 with polyubiquitinated NEMO, forms a complex with MCPIP1 and USP10. The TANK-
which in turn removes the linear ubiquitin chains from associated USP10 is required for the decrease of
NEMO and suppresses NF-kB signaling upon DNA TRAF6 polyubiquitination, which in turn diminishes
damage. Two N-terminal domains of MCPIP1 are the NF-kB activation by DNA damage. Therefore,
essential for MCPIP1 to direct USP10-dependent USP10 is able to efficiently terminate DNA damage-
deubiquitination. The RNase-CCCH domain is required induced NF-kB activation through attenuating two
for interaction between MCPIP1/NEMO/USP10 and critical ubiquitin events, linear ubiquitination of NEMO
the UBA domain is required for MCPIP1 binding to and K63-ubiquitination of TRAF6, in genotoxic NF-kB
ubiquitin chains, which may present the ubiquitinated signaling. In addition to genotoxic stress, the TANK-
substrates to USP10 for cleavage. [112] Consistently, NF- MCPIP1-USP10 complex is also responsible for
kB-dependent gene transcription upon DNA damage restraining TRAF6 ubiquitination in cells treated with
was significantly enhanced in MCPIP1-deficient cells. LPS or IL-1β. Altogether, these data support that TANK
Therefore, induction of MCPIP1 serves as a negative may also serve as a negative regulator of genotoxic
52 Journal of Cancer Metastasis and Treatment ¦ Volume 3 ¦ March 27, 2017