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Tumor Discovery RNA-protein complexes deregulated in cancer

and dissolve, providing cells with a mechanism to create as well as Coulomb interactions with the phosphate
temporary compartments. This allows biomolecules to groups of nucleic acids. PTMs, including tyrosine and
be released and relocated when no longer needed at a serine phosphorylation and arginine methylation,
specific site. Furthermore, compartmentalization within regulate LLPS. Arginine methyltransferases methylate
15
condensates helps stabilize protein concentrations in cells, the charged guanidine group of arginine, altering or
acting as a buffer against the inherent stochasticity of gene inhibiting the electrostatic interactions required for phase
expression. 16-18 separation. PTMs often accelerate LLPS by facilitating
biorecognition, conformational changes, electrostatic
2.1. Interactions between amino acids of protein interactions, and local accumulation of negative charges.
partners and the role of post-translational Lysine ubiquitination increases Tau’s propensity to form
modification (PTM) BCs but weakens Tau/RNA interactions. Conversely, lysine
In the nucleus, chromatin subdomains can undergo liquid– acetylation reverses LLPS, reducing Tau’s localization
liquid phase separation driven by the IDRs of histone tails, in SGs. Tau acetylation blocks phase transition by
leading to the formation of dense and dynamic droplets. neutralizing lysine-positive charges, thereby interrupting
Various proteins contribute to the aberrant formation of the electrostatic interactions between Tau residues and
protein aggregates. These proteins often contain prion- microtubules. Heterogeneous ubiquitination stabilizes
like domains (PrLDs) enriched in uncharged polar amino droplets against dissolution. 24-26 Tau undergoes LLPS with
acids, such as asparagine, glutamine, tyrosine, and glycine, DNA, mononucleosomes, and nucleosome arrays under
which are essential for phase separation. One such protein low-salt conditions and localizes within droplets formed
is fused in sarcoma (FUS), which can self-assemble in by nucleosomes and phosphorylated HP1α. Aberrant Tau
paraspeckles. FUS, similar to TAR DNA-binding protein hyperphosphorylation disrupts chromatin interactions
43 (TDP-43), contains IDRs and PrLDs that drive protein and LLPS formation. PTMs and RNA and protein
26
aggregation within SGs, as observed in neurodegenerative modifications can influence condensate behavior. 24-26
diseases. 12,14,16 The tumor suppressor p53 protein is prone
to amyloid-like aggregation, especially in its mutated 2.2. ncRNAs and small RNAs
forms, and the p53-MDM2 interaction is influenced by the Cellular RNA transcripts include mRNAs, rRNAs,
presence of IDRs. Tau protein, which localizes in SGs and tRNAs, and ncRNAs. Small RNAs include microRNAs
is relevant to Alzheimer’s disease development, can also (miRNAs), which are 22 nucleotides in length and play
undergo LLPS. roles in the post-transcriptional control of target mRNAs,
Oppositely charged species regulate condensate small interfering RNAs (SiRNAs), trans-acting small
formation based on RNA levels: low RNA levels promote interfering RNAs (tasi-RNAs), and small nucleolar RNAs
formation, while excessive RNA levels trigger dissolution. (sno-RNAs). Non-small RNAs include circular RNAs,
Transcription and condensates create a feedback loop noncapped RNAs (nap-RNAs), which are involved in
where short-lived RNA enhances condensate formation, gene expression regulation, and ncRNAs exceeding 500
and high RNA levels induce dissolution. 17,19 The phase nucleotides in length.
separation of RNA-binding proteins depends on RNA The majority of transcribed RNAs are functional. 27,28
length. RNA structure determines dense-phase identity Studies on RNA have employed siRNA libraries for high-
20
within BCs. For instance, Whi3, an ER-associated protein throughput silencing of many ncRNAs as well as chromatin
with a C-terminal RNA recognition motif (RRM), forms immunoprecipitation and RNA immunoprecipitation
distinct RNA granules based on RNA structural differences, (RNA-IP) methods combined with next-generation
demonstrating RNA specificity. 21 sequencing to explore RNA functionality. RNA
28
Lysines play a significant role in the condensation of BCs. modifications, such as 5′-end capping and polyadenylation
This was studied in Alzheimer’s-associated Tau protein, (polyA tails), are essential for RNA localization and
which exhibits a distinct phase separation mechanism function. In addition, RNAs undergo epigenetic
compared with Tau/RNA coacervation. Ukmar-Godec modifications, including those mediated by adenine
22
et al. explored the role of lysine in disordered protein deaminase and nucleotide-methylating enzymes. 27,29 These
23
regions within P bodies, highlighting its ability to drive RNA modifications are transient and include methylation
phase separation and form lysine/RNA coacervates. of adenine (m6A, m1A), cytosine (m6C), and guanine
Glycine enhances fluidity, whereas glutamine and serine (m7G) as well as acetylation of adenine (ac4A). 27,30-32 These
promote hardening. Amino acids such as arginine modifications can alter base pairing, reduce the affinity for
exhibit distinct properties in protein condensates, such complementary sequences, or mask target sites on proteins
as cation–π interactions between tyrosine and arginine or mRNAs.

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