All organisms must safeguard the integrity of their DNA to avoid deleterious consequences of genome instability, which have been linked to human diseases such as autoimmune disorders, neurodegenerative diseases and cancer. Traditionally, genome maintenance has been viewed largely in terms of DNA–protein interactions. However, emerging evidence points to RNA as a key modulator of genome stability, with seemingly opposing roles in promoting chromosomal instability and protecting genome integrity. Unravelling the mechanistic and contextual basis of this duality will not only improve our understanding of the interfaces between RNA and the genome but will also provide important insights into how disrupted RNA metabolism contributes to disease origin, laying the foundation for targeted intervention.
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The authors thank S. John and N. Johnson for critical reading of the manuscript. The authors acknowledge and apologize to peers whose work could not be cited owing to space limitation.
The authors declare no competing interests.
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A large ensemble of proteins that together create a replication fork and initiate DNA synthesis from a replication origin.
- Nucleolytic cleavage
A chemical or enzymatic process that breaks phosphodiester bonds in the DNA backbone.
- Structure-specific nucleases
Enzymes that recognize and cleave specific types of secondary structure within DNA.
- Nucleotide excision repair
A mode of DNA repair wherein a string of nucleotides containing the damaged bases are excised and the resultant gap is filled in by new DNA synthesis.
- Transition mutations
A type of point mutation that changes a purine nucleotide to another purine or a pyrimidine nucleotide to another pyrimidine.
- Immunoglobulin class switch recombination
A physiological gene rearrangement event in B lymphocytes that replaces the heavy-chain constant region of the expressed immunoglobulin isotype with a different heavy-chain constant region, thereby altering the effector function of the antibody.
- CpG islands
Distinct regions of the genome that contain a large number of predominantly unmethylated CG dinucleotide repeats, which are frequently found near mammalian gene promoters.
- Promoter-proximal pausing sites
Regions near the promoter of genes where RNA polymerase pauses until it is stimulated to resume transcriptional elongation.
- Gene gating
The process of tethering genes to nuclear pore complexes, which enables rapid RNA maturation and export.
- Gene conversion
A homology-directed DNA recombination event wherein a resected double-strand break invades the intact sister chromatid and uses it as a template to restore sequences around the break site.
- Single-strand annealing
A mutagenic form of DNA repair wherein repetitive regions on either side of a double-strand break are converted into single-stranded DNA by end resection and annealed to one another, resulting in the deletion of the intervening sequences.
- Break-induced replication
A non-reciprocal DNA recombination event wherein a resected one-ended double-strand break invades an intact genomic region and initiates long-range unidirectional templated DNA synthesis that typically proceeds to the end of the invaded chromosome.
- Synthetic lethality
A condition where combined deficiencies in two or more genes result in cell death, while perturbation of any one of these genes is tolerated.
- Phase separation
The separation of a single homogeneous mixture into two distinct phases.
A macromolecular complex consisting of both RNA and protein.
A large multisubunit ribonucleoprotein complex that removes introns from a precursor mRNA transcript.
- trans splicing
An RNA splicing event in which exons of two disparate precursor mRNAs are joined together into a single chimeric transcript.
- cis splicing of adjacent genes
An event in which two neighbouring genes are read as a single message due to readthrough transcription followed by intergenic splicing.
Pertaining to RNA modifications that potentially regulate gene expression but that do not involve alterations in the primary ribonucleotide sequence.
- Translesion synthesis
A DNA damage tolerance mechanism that enables DNA synthesis past replication-blocking DNA lesions.
- Base excision repair
A mode of repair that removes a small, non-helix-distorting base lesion from the genome, leaving an abasic site that is subsequently cleaved and filled in by either non-displacement (short-patch) or strand-displacement (long-patch) DNA synthesis.
- Topologically associated domain
(TAD). A genomic domain created by chromosome folding that favours chromatin interactions within its borders.
- CTCF-mediated chromatin looping
A process by which CTCF binding to DNA facilitates long-range chromatin interactions between regions that are far apart on the linear chromosome.
- RNA–DNA triplex
A form of RNA–DNA interaction in which the RNA strand inserts itself into the major groove of the duplex DNA in a sequence-specific manner.
- RNA exosome
A multiprotein ribonuclease complex capable of degrading various types of RNA molecule.
A multicomponent ribonuclease complex that degrades mitochondrial RNA.
- Slipped-strand mispairing
Erroneous base pairing in regions of repetitive DNA due to sequence misalignment, resulting in a short stretch of unpaired nucleotides that form a bulge in the DNA.
- Non-allelic recombination
A DNA recombination event between any two regions in the genome that have a high degree of sequence homology but are not alleles.
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Zong, D., Oberdoerffer, P., Batista, P.J. et al. RNA: a double-edged sword in genome maintenance. Nat Rev Genet (2020). https://doi.org/10.1038/s41576-020-0263-7