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Tumor Discovery RNA-protein complexes deregulated in cancer

Table 4. ncRNAs required for the formation of biomolecular condensates (BCs) or interaction with protein components
Type ncRNA Interactome Deregulated in cancer
Speckle MALAT1 DBC1, PRPF6, SRSF, hnRNPs, ELAVL1/HuR Breast cancer, CRC 102
Paraspeckle NEAT1_2 NONO, SFPQ, and PSPC1 Triple-negative BC, HCC 103
PML body DUXAP8 PTEN Prostate, ovary, bladder, breast, pancreas, RCC, GC 48
Stress granules (SGs) RP11-435F13.2 ELAVL1 (HuR) Pancreatic and esophageal cancer 57
SG NORAD ALKBH5, AGO, DDX6 Various cancers 57
Abbreviations: AGO: Argonaute; ALKBH5: ALKB homolog 5, erasing m6A; BC: Breast cancer; CRC: Colorectal cancer; DBC1: Depleted in breast
cancer; DDX6: Death box family RNA-dependent helicase ATPase 6; DUXAP8: Double homeobox A pseudogene 8; GC: Gastric cancer; HuR:
Human R antigen; MALAT1: Metastasis-associated lung adenocarcinoma transcript 1; NEAT1: Nuclear enhanced paraspeckle assembling transcript
1; NORAD: Noncoding RNA activated by DNA damage; PML: Promyelocytic leukemia; PRPF6: Pre-mRNA-processing factor; RCC: Renal cell
carcinoma; SRSF: Serine/arginine-rich splicing factors.

genes through interactions with proteins that guide this SIM and SUMOylation sites. This alteration impairs PML
RNA to nascent pre-mRNAs. MALAT1 functions as a phase separation, causing dispersed microspeckles and
scaffold for speckle proteins, facilitating the positioning of concentrating transcriptional machinery at oncogenes,
nuclear speckles at active gene loci. potentially impacting RNA splicing and contributing to
oncogenesis. Novel therapeutic approaches targeting PML
3.2. PML bodies, p53 guardian of the genome, and in cancer have been recently reviewed. 148
cancer
Condensates are regulated at multiple levels, with
PML bodies are dynamic nuclear MLO compartments alterations in their properties influencing their formation,
145
that compartmentalize diverse proteins, such as p53 and viscoelasticity, dissolution, and other physicochemical
DNA repair protein complexes. PML bodies regulate aspects, ultimately modifying their functions. Several
various cellular processes, including apoptotic pathways factors are critical for the regulation of BCs. Dysregulation
and genome stability. Failures in DNA damage repair in the concentration of components, chemical
(DDR) result in chromosomal instability, a hallmark of modifications, involvement of ncRNAs, and selective
cancer. Various ncRNAs contribute to DNA stability and partitioning are observed in cancer cells. Among these,
repair, which are essential processes in cancer development. the concentration of biomolecules is a pivotal parameter

PML bodies participate in activities such as transcription in condensate dynamics. Condensation occurs when a
regulation, cell cycle control, antiviral defense, and critical threshold concentration is reached, which can
apoptosis promotion. These functions are mediated by be achieved through protein accumulation, inhibition of
PTMs, such as phosphorylation by protein kinase 2 (PK2) degradation, confinement within a membrane-bound
and deubiquitination by USP7/HAUSP, which regulate compartment, or sequestration by binding to a substrate
protein ubiquitination for proteasomal degradation. PML with multiple binding sites. Notably, the dissolution of
bodies are also targeted by various oncolytic viruses. The condensates occurs during mitosis when the loss of the
146
Momordica anti-HIV protein MAP30 has been shown to nuclear membrane reduces the concentration of nuclear
decrease HBV replication by inhibiting EBNA1, which components. Condensates reform in the nucleus once
directs PML proteins to degradation and promotes PML the nuclear envelope is re-established, facilitated by an
loss. 147 increase in component concentrations through protein

Among the tripartite motif (TRIM) proteins, which transport into the nucleus. Alterations in BCs are pervasive
include a series of RING-type E3 ligases, the TRIM in cancer and are driven by diverse stresses within the
19 protein is encoded by PML. The N-terminal RBCC tumor microenvironment. The phase separation of cancer-
(RING, B-Box 1/2, coiled-coil) domain facilitates PML associated proteins influences numerous cellular processes,
protein scaffold self-oligomerization. The C-terminus contributing to cancer development.
contains small ubiquitin-like modifier (SUMO) sites One notable role of ncRNAs interacting with
and a SUMO-interacting motif (SIM), which enhance condensates involves the activation of the tumor suppressor
granule assembly through SUMO and SIM arrays, protein p53 and its downstream signaling pathways.
149
promoting liquid-like condensate formation. In cancer, The p53 protein is prone to amyloid-like aggregation,
PML bodies exhibit diverse roles. In acute promyelocytic particularly in its mutated forms. Interactions between
leukemia (APL), chromosomal translocation results in p53 and MDM2, an E3 ubiquitin ligase that degrades p53,
the fusion protein PML-RARα, which lacks C-terminal are influenced by IDRs. MDM2 inhibits p53 by inducing

Volume 3 Issue 4 (2024) 10 doi: 10.36922/td.4657