Cells encounter a multitude of external and internal stress-causing agents that can ultimately lead to DNA damage, mutations and disease. A cascade of signaling events counters these challenges to DNA, which is termed as the DNA damage response (DDR). The DDR preserves genome integrity by engaging appropriate repair pathways, while also coordinating cell cycle and/or apoptotic responses. Although many of the protein components in the DDR are identified, how chemical modifications to DNA impact the DDR is poorly understood. This review focuses on our current understanding of DNA methylation in maintaining genome integrity in mammalian cells. DNA methylation is a reversible epigenetic mark, which has been implicated in DNA damage signaling, repair and replication. Sites of DNA methylation can trigger mutations, which are drivers of human diseases including cancer. Indeed, alterations in DNA methylation are associated with increased susceptibility to tumorigenesis but whether this occurs through effects on the DDR, transcriptional responses or both is not entirely clear. Here, we also highlight epigenetic drugs currently in use as therapeutics that target DNA methylation pathways and discuss their effects in the context of the DDR. Finally, we pose unanswered questions regarding the interplay between DNA methylation, transcription and the DDR, positing the potential coordinated efforts of these pathways in genome integrity. While the impact of DNA methylation on gene regulation is widely understood, how this modification contributes to genome instability and mutations, either directly or indirectly, and the potential therapeutic opportunities in targeting DNA methylation pathways in cancer remain active areas of investigation.
5-Methylcytidine (m C) and 5-methyluridine (m U) are highly abundant post-transcriptionally modified nucleotides that are observed in various natural RNAs. Such nucleotides were labeled through a chemical approach, as both underwent oxidation at the C5=C6 double bond, leading to the formation of osmium-bipyridine complexes, which could be identified by mass spectrometry. This osmium tag made it possible to distinguished m C and m U from their isomers, 2'-O-methylcytidine and 2'-O-methyluridine, respectively. Queuosine and 2-methylthio-N -isopentenyladenosine in tRNA were also tagged through complex formation.
Nearly 200 distinct chemical modifications of RNAs have been discovered to date. Their analysis via direct methods has been possible in abundant RNA species, such as ribosomal, transfer or viral RNA, since several decades. However, their analysis in less abundant RNAs species, especially cellular messenger RNAs, was rendered possible only recently with the advent of high throughput sequencing techniques. Given the growing biomedical interest of the proteins that write, erase and read RNA modifications, ingenious new methods to enrich and identify RNA modifications at base resolution have been implemented, and more efforts are underway to render them more quantitative. Here, we review several crucial modification-specific (bio)chemical approaches and discuss their advantages and shortcomings for exploring the epitranscriptome.
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