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Tumor Discovery RNA-protein complexes deregulated in cancer

its degradation and blocking its transcriptional activity, 3.3. Microspeckles and superenhancers
whereas p53 induces MDM2 expression, forming a Recent research has revealed that gain-of-function
regulatory feedback loop. In the DNA repair pathway, mutations in the miR-1400 seed sequence, caused by
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phase-separated DNA repair foci containing the DNA chondrocyte-activated superenhancers, lead to skeletal
damage-response factor p53-binding protein 1 (53BP1) dysplasia, emphasizing the role of superenhancers in
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also concentrate p53 protein. Disruptions in these phase- disease mechanisms. While the correlation between
separated foci impair the 53BP1-dependent induction of superenhancers and ncRNAs in controlling cell identity
p53, reducing the expression of p53 target genes. Among remains underexplored, it is proposed that super-
the transcripts activated by p53, 152-154 several ncRNAs, enhancer-driven ncRNAs (SE-ncRNAs) are associated with
such as LINC1, Guardin, and NEAT1_2, play significant tumor development and pathogenesis. RNA molecules
roles, in addition to 53BP1. 155-157 facilitate condensate formation, initiate transcription,

Since p53 acts as a tumor suppressor, its altered and contribute to the fusion or pairing of enhancer
activity due to mutations, reduced concentration, or condensates with promoter sites, leading to transcriptional
impaired signaling at DNA repair foci can promote cancer bursts. RNA-mediated feedback may terminate these
progression. In response to DNA damage, different repair transcriptional bursts, highlighting the roles of ncRNAs
mechanisms are activated depending on the type of near enhancers or promoters. 91,93,94 Interactions between
damage. Double-strand breaks are repaired by mechanisms such RNAs and enhancers could regulate the rate and
such as homologous recombination (HR), classical magnitude of transcriptional bursts. The accumulation
non-homologous end-joining (NHEJ), alternative end- of ncRNA near genes may influence condensate size or
joining, and single-strand annealing. Larger nucleotide dissolution through feedback mechanisms. Furthermore,
adducts are repaired through nucleotide excision repair, ncRNAs can modulate transcription by interacting with
whereas smaller base lesions are repaired through base CTCF (CCCTC-binding factor), stabilizing genomic
excision repair. LINP1 ncRNA assembles proteins such boundaries, and limiting the territory over which an
as RPA, Ku70, Ku80, and ISWI, bringing in proximity enhancer or super-enhancer operates. 164,165 Functional
breast cancer type 1 susceptibility protein (BRCA1), PAR crosstalk between superenhancers and ncRNAs—spanning
polymerase 1 (PARP1), cadherin 4 (CDH4), and 53BP1. gene regulation in cis and trans and the regulation of
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NIHCOLE RNA acts as a scaffold for proteins, interacting superenhancers by ncRNAs—has also been proposed.
with multiple Ku80 units and promoting phase separation, Noncoding mutations play a significant role in the
facilitating the formation of multimeric NHEJ complexes to dysregulation of superenhancers in cancer. For example, in
optimize ligation efficiency. It supports repair complexes approximately 5% of T-cell acute lymphoblastic leukemias
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like the XRCC4-DNA Ligase IV ligation complex. Another (T-ALL), small insertions near the TAL1 gene induce
ncRNA, LRIK, binds to Ku70 – Ku80 heterodimers. ectopic super-enhancer creation. This presents a working
hypothesis for studying how noncoding mutations trigger
SNHG12 RNA stabilizes the interaction between 165
DNA-PK and Ku70/Ku80, promoting NHEJ-based DNA ectopic super-enhancer establishment. Drugs targeting
BCs, such as cyclopamine (a steroidal alkaloid ) and
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repair. HITT RNA binds to ataxia-telangiectasia mutated nucleolin, could enable the pharmacological modulation
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(ATM) and prevents the formation of the MRE11-RAD50- of oncolytic virus replication and control transcription
NBS1 (MRN) complex, playing a role in both HR and factors at cancer-driving superenhancers.
NHEJ. 160
Protein–protein interactions are crucial for assembling 3.4. SGs
DNA repair complexes. BRCA1, through its leucine-zipper Key components of SGs include the Ras-GTPase-activating
domain, interacts with PARP1, which performs poly-ADP- protein (GAP) SH3 domain-binding proteins G3BP1 and
ribosylation, creating PAR chains that recruit PAR-binding G3BP2, which are pivotal in cell behavior and cancer. 13,168,169
proteins. MALAT1 forms a complex with PARP1 and DDX3, a DEAD-box RNA helicase and RNA-binding
ligase 3 (LIG3), facilitating HR. Inhibiting this complex has protein, localizes with DDX6 to SGs alongside Gle1A,
170
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shown therapeutic benefits in prostate cancer and multiple a DDX regulator, and CAPRIN1. DDX3 is essential for SG
myeloma. 161,162 H19, an ncRNA silenced in clonal sheep assembly, which occurs through nucleation mediated by
reproduction, increases BRCA1 stability by interfering the RNA decay factor G3BP1. G3BP1 prevents ribosome
with BRCA1 degradation mediated by ubiquitin ligases and initiation factor localization in silenced SG foci,
HUWE1 and UBE2T. Silencing H19 disrupts the DNA assisted by other SG-associated proteins, such as DDX3,
repair process and enhances sensitivity to PARP inhibitors DDX6 (Rck/p54), Y-box-binding protein (YBX1/YB-1),
(PARPi), offering potential therapeutic advantages. 163 translational suppressors TIA1 and TIAR, CAPRIN1,

Volume 3 Issue 4 (2024) 11 doi: 10.36922/td.4657