Page 55 - Read Online

Wang et al. Genotoxic NF-kB activation in cancer

generally termed DNA damage response. DNA PKcs is constitutively associated with Tip60, which
[4]
double-strand breaks could be recognized and bound controls its activity. Knockdown of Tip60 by siRNA
by a protein complex called MRE11/RAD50/NBS1 reduces the phosphorylation and activation of DNA-
(MRN) within a few seconds of their formation. As a PKcs in response to bleomycin. [38] Most DNA-PK
DSB lesion sensor, MRN complex binds to the break substrates are implicated in DNA repair (DNA-PK
extremities, stabilizes them close to each other and itself, Artemis, polynucleotide kinase, XLF, excision
initiates DDR via NBS1-dependent recruitment of repair cross complementing 4), whereas DNA-PK-
ATM kinase. [23-25] In resting cells, inactive ATM dimer dependent phosphorylation of H2AX, KAP-1, p53
associates with the Tip60 histone acetyltransferase leads to activation of cell death machinery. [39,40] As
and protein phosphatase 2A. [26,27] Upon DNA damage, a replication stress sensor binding to single-strand
MRN complexes bound to DNA breaks recruit Tip60 DNA, heterotrimeric Replication Protein A (RPA)
on histone 3 trimethylated on K9 (H3K9me3). This accumulates at stalled replication forks and recruits
interaction activates Tip60 which in turn acetylates ATR interacting protein (ATRIP) in association with
ATM kinase on K3016. [28,29] ATM acetylation induces ATR kinase. Activation of ATR also requires Rad9/
its confirmation change and auto phosphorylation on Rad1/Hus1 heterotrimer (9-1-1 complex) and the DNA
[41]
S367, S1893, S1981 and S2996 as well as dimer-to- topoisomerase binding protein 1 (TopBP1). ATR
monomer transition. [30-32] The dissociation of protein kinase activity is necessary for stabilization and restart
phosphatase 2A, which targets phosphorylated S1981, of stalled replication forks, and for signaling to cell cycle
from ATM is also required for full activation of ATM. [27] checkpoint activation. [42,43] Therefore, ATR is essential
for cell replication and viability as well as maintaining
Around 10% of activated ATM by irradiation or genomic stability. [44,45]
neocarzinostatin treatment associates with chromatin
in the form of ionizing radiation induced foci (IRIF), NF-kB ACTIVATION IN DNA DAMAGE
whereas the majority of active ATM remains free in RESPONSE
nucleoplasms. [33,34] As a master regulator of the DSB-
induced DDR, ATM phosphorylates various substrates Besides the prompt cellular responses (e.g. cell
at the consensus target sequence, (S/T)Q, so as to cycle arrest, DNA repair) to counteract DNA lesions,
orchestrate the activation of multiple signaling pathways transcription/expression of a large number of genes
regulating cell cycle arrest, DNA repair, and apoptosis can also be altered in response to DNA damage. Two
[35]
as well as other pathophysiological processes. ATM transcription regulators, p53 and NF-kB, have been
substrates can be divided into subsets based on their identified as the major players for reprogramming
subcellular localization, such as chromatin-associated the transcription of these genes in response to
(H2AX, KAP1), integrated in the IRIF (MDC1, 53BP1, IR. [46-48] DNA damage-dependent regulation of p53
BRCA1, NBS, MRE11, RNF20-RNF40), IRIF-adjacent signaling has been well studied and comprehensively
and phosphorylated by IRIF-bound ATM (Chk2), reviewed. [2,49,50] Here we focus on the recent progress
or phosphorylated by a free-floating pool of ATM in understanding genotoxic stress-induced NF-kB
(p53, NEMO) in nucleoplasm. Beyond those nuclear signaling.
substrates, a subset of ATM substrates localized in the
cytoplasm (4EBP1, TAB2) has also been reported to NF-kB family
play critical roles in cellular response to DSBs. [2,4] NF-kB is a family of transcription factors composed
of five members, p65 (RelA), c-Rel, RelB, p105/p50
ATM belongs to a family of PI3K-related protein and p100/p52, which form hetero- or homo-dimers and
kinases which includes ATM, ATR, DNA-PKcs, mTOR, regulate a variety of physiological and pathological
SMG-1 and TRRAP. Although they all share the processes. In resting cells, NF-kB localizes in the
[4]
similar kinase domain as that in lipid kinase PI3K, they cytoplasm in association with a family of inhibitor
are protein kinases except for TRRAP whose kinase proteins called IkBs (inhibitor of NF-kB), such as
activity remains to be validated. Along with ATM, DNA- IkBα. [11,51] Upon stimulation, NF-kB is released from
PK and ATR also play essential roles in mediating IkBs and translocates into the nucleus, where it binds
DNA damage response. In human cells, most breaks to the promoter and/or enhancer regions of its target
are rapidly repaired by cNHEJ throughout the entire genes and regulates their transcription. In addition to
cell cycle. [17,36] DNA-PKcs is indispensable for repairing nuclear translocation, posttranslational modification
DNA double-strand breaks by NHEJ. DNA-PKcs can of NF-kB, such as phosphorylation, acetylation and
be recruited to DSBs by the Ku70/Ku80 heterodimer methylation of p65, also plays a significant role in
and form the active DNA-PK complex, which promotes modulating transcriptional activity. [11,52] A large number
synapsis of the broken DNA ends. Like ATM, DNA- of NF-kB-target genes have been identified (see list
[37]
Journal of Cancer Metastasis and Treatment ¦ Volume 3 ¦ March 27, 2017 47