RESUMO
N6-methyladenosine (m6A) is one of the most prevalent internal reversible chemical modification of RNAs in eukaryotes, which has attracted widespread attention recently owing to its regulatory roles in a plethora of normal developmental processes and human diseases like cancer. Deposition of the m6A mark on RNAs is mediated by the dynamic interplay between m6A regulatory proteins such as m6A RNA methyltransferases (m6A writers), m6A RNA demethylases (m6A erasers) and m6A RNA binding proteins (m6A readers). m6A regulators are ectopically expressed in various cancer types, often leading to aberrant expression of tumor-suppressor and oncogenic mRNAs either directly or indirectly via regulating the biogenesis of non-coding RNAs like miRNAs. miRNAs are tiny regulators of gene expression, which often impact various hallmarks of cancer and thus influence tumorigenesis. It is becoming increasingly clear that m6A RNA modification impacts biogenesis and function of miRNAs, and recent studies have interestingly, uncovered many miRNAs whose biogenesis and function are regulated by m6A writers, erasers and readers. In this review, we discuss various mechanisms by which m6A RNA methylation regulates miRNA biogenesis, the functional crosstalk between m6A RNA methylation and miRNAs and how it modulates various aspects of tumorigenesis. The potential of m6A RNA methylation regulated miRNAs as biomarkers and novel therapeutic targets to treat various cancers is also addressed.
RESUMO
Cellular RNAs, both coding and noncoding are adorned by > 100 chemical modifications, which impact various facets of RNA metabolism and gene expression. Very often derailments in these modifications are associated with a plethora of human diseases. One of the most oldest of such modification is pseudouridylation of RNA, wherein uridine is converted to a pseudouridine (Ψ) via an isomerization reaction. When discovered, Ψ was referred to as the 'fifth nucleotide' and is chemically distinct from uridine and any other known nucleotides. Experimental evidence accumulated over the past six decades, coupled together with the recent technological advances in pseudouridine detection, suggest the presence of pseudouridine on messenger RNA, as well as on diverse classes of non-coding RNA in human cells. RNA pseudouridylation has widespread effects on cellular RNA metabolism and gene expression, primarily via stabilizing RNA conformations and destabilizing interactions with RNA-binding proteins. However, much remains to be understood about the RNA targets and their recognition by the pseudouridylation machinery, the regulation of RNA pseudouridylation, and its crosstalk with other RNA modifications and gene regulatory processes. In this review, we summarize the mechanism and molecular machinery involved in depositing pseudouridine on target RNAs, molecular functions of RNA pseudouridylation, tools to detect pseudouridines, the role of RNA pseudouridylation in human diseases like cancer, and finally, the potential of pseudouridine to serve as a biomarker and as an attractive therapeutic target.
