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Tumor Discovery RNA-protein complexes deregulated in cancer

2.3. ncRNAs are required for LLPS, BC formation, In the formation of local condensates, ncRNAs can
and BC activity assemble proteins into chromatin-regulating complexes 33,34
ncRNAs, polyadenylated or nonpolyadenylated, perform and DNA damage repair complexes. 35
diverse genome-regulatory functions, including encoding In the following paragraphs, the roles of ncRNAs in
of micropeptides and miRNAs as well as acting as cancer development will be described from the perspective of
decoys for DNA–protein interactions. For example, p21- potential therapeutic approaches. RNA–protein complexes
associated RNA DNA damage-activated (PANDA) acts as determine local LLPS and regulate cellular physiology
a decoy for nuclear transcription factor Y subunit-α (NF- and pathology. Local compartmentalization within BC
YA), sequestering NF-YA from target gene promoters. loci is a critical determinant that facilitates the high local
ncRNAs can also function as miRNA sponges, sequestering concentration of biomolecules and their substrates while
miRNAs away from their mRNA targets. Both linear excluding functionally irrelevant molecules.
ncRNAs and circular RNAs (circRNAs) function as RNA Specific pathways and cellular responses that determine
sponges and compete endogenous RNAs (ceRNAs). LLPS formation and function include mRNA transcription,
CircRNAs are deregulated in various cancers (https:// mRNA splicing in speckles and paraspeckles, orchestration
ngdc.cncb.ac.cn/circatlas/disease.php) and primarily of chromatin domains, the DNA damage response in the
function as RNA sponges, influencing target miRNAs nucleus, and stress responses through the formation of
based on cell type and miRNA expression profiles. The SGs in the cytoplasm. Unique ncRNAs are essential for the
mechanism involves the interaction of three partners: formation of certain BCs. For instance, NEAT1_2 is crucial
circRNA/miRNA/protein target. miRNAs downregulate for paraspeckle formation, whereas MALAT1 is recruited
mRNA and target protein levels, whereas circRNAs to speckles through interactions with multiple splicing-
block miRNAs through complementarity. Increased associated proteins, although it is not essential for speckle
levels of miRNAs reduce target protein levels by blocking formation. These BCs, including speckles and paraspeckles,
or degrading target mRNAs. Similar to ncRNAs, play vital roles in transcription and splicing. Specific
circRNAs may act as decoys, protecting amino acids in pathways and cellular responses, such as the formation of
interacting partners from modifications or degradation euchromatin and heterochromatin and the activation or
or sequestering partners to prevent interactions with silencing of genes, rely on LLPS. These events occur through
other proteins. These interactions are stoichiometric for riboprotein complexes involved in assembling histone locus
ceRNAs and super-stoichiometric for RNA sponges. RNA bodies and other BCs associated with chromatin regulation.
sponges and RNA decoys are not discussed further here. In the nucleus, chromatin subdomains can undergo liquid–
CircRNAs, devoid of a 5′-cap structure and a 3′ poly(A) liquid phase separation driven by the IDRs of histone tails.
tail, are generated through a back-splicing process and This process results in the formation of dense, dynamic
can be translated through 5′ cap-independent internal droplets, including histone locus bodies.
translation initiation. In some cases, circRNAs are
produced from protein-coding genes, such as circBRD7, A significant number of ncRNAs function in concert
derived from the bromodomain protein BRD7. Adenine with protein complexes to guide chromatin-modifying
methylation (m6A) modifications occur in ncRNAs, complexes to genomic sites. Polycomb (PcG) repressive
circRNAs, and protein-coding mRNAs. However, complexes (PRC1 and PRC2) are involved in gene
circRNA m6A methylation is more variable and occurs silencing, while mixed-lineage leukemia 1 (MLL)
randomly, whereas ncRNA m6A methylation is more complexes promote gene activation. PRC2 represses
stable and tumor-type specific. Specific cases of circRNA genes by depositing repressive histone marks, such as
functioning in the epigenetic regulation of transcription H3K27me3 and H3K9me3, which lead to the formation
and its relationship with m6A modifications in cancer of heterochromatin. Conversely, activating complexes
will be discussed in the following sections. RNAs have deposit marks like H3K4me3 and H3K36me3, facilitating
been found to act as oncogenes, contributing to cell euchromatin formation. NcRNAs that serve as scaffolds for
proliferation and activation of oncogenic signals through chromatin-modifying complexes guide these complexes
overexpression or increased stability. Conversely, RNAs to target genomic loci. In other cases, ncRNAs prevent
can function as tumor suppressors, blocking oncogenic chromatin-modifying complexes from recognizing specific
signaling depending on the cellular context and specific gene promoters.
functions (e.g., sponging oncogenic miRNAs, silencing Histone marks are recognized by enzyme readers,
promoters of genes involved in cell cycle regulation, including chromodomain, Tudor domain, PWWP domain,
proliferation, or antiapoptotic function). These tumor- and PHD domain-containing enzymes. Bromodomain-
suppressive RNAs are often downregulated in tumors. containing protein 4 (BRD4) is an acetylated histone reader

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