Transcription: friend or foe of genome stability

Abstract

Over the past 60 years, tremendous progress has been made in elucidating the highly regulated process of transcription, a cellular mechanism during which RNA polymerases copy specific DNA sequences into RNA. Initially considered as simple messengers between DNA and protein synthesis, it is now undeniable that RNA transcripts play fundamental roles in various aspects of DNA metabolism, ranging from gene expression regulation to chromatin remodelling [[1, 2]]. Furthermore, a convergence of molecular and genomic evidence reveal that pre-existing RNA and de novo RNA may directly or indirectly contribute to DNA damage signalling pathways and preservation of genome integrity [[3]]. This is well-illustrated by the long noncoding telomeric repeat-containing RNA (TERRA), which directly participates in genomic integrity by contributing to telomere maintenance [[4-6]]. Besides the genome-protective function of RNAs, the transcriptional process itself is crucial for genome maintenance. By unwinding and scanning the DNA double helix, the transcription process contributes towards the identification and repair of a wide variety of DNA lesions. Indeed, impediments of transcription elongation caused by DNA lesions result in stalling of RNA polymerases, whose outcome can be detrimental to cell survival. The stalling of RNA polymerases can nevertheless promote the recruitment of DNA repair machineries to the damaged sites. Depending on the nature of the lesions, a wide variety of transcription-coupled repair mechanisms thus exist, which enable efficient repair of transcribed regions as well as fast restart of transcription after genotoxic stress [[7-11]].

However, transcription can also be a source of genomic instability. Indeed, it can directly induce DNA damage by generating torsional stress on the double helix structure or exposing single-strand DNA to genotoxic agents [[12]]. In addition, a collision between transcription and other processes occurring on DNA, such as DNA replication, may have a nefarious outcome on genome integrity [[13]]. Both transcription and DNA replication machineries are large multiprotein assemblies that cannot simultaneously stand on the same DNA strand. Their collision gives rise to conflicts that, if not properly resolved, may result in transcription and replication stalling as well as the generation of DNA double-strand breaks (DSBs) [[13, 14]]. Furthermore, the unwinding of guanine (G)-rich DNA sequences during transcription may result in the formation of stable noncanonical DNA structures, such as G-quadruplexes (G4), which normally contribute to transcription as well as telomere maintenance, recombination and epigenetic regulation [[15]]. However, depending on their localization or persistence, the G4 structures may induce genome instability by causing DNA breaks. Similarly, transcription of GC-rich DNA sequences can induce the formation of R-loops, three-stranded structures formed by a RNA:DNA hybrid and the associated non-template single-stranded DNA [[16]]. These transcriptional by-products play a relevant role in gene expression regulation, but their unscheduled formation or unprocessing may threaten RNA polymerase elongation, thus leading to transcriptional stress and DNA breaks [[17-19]].

In conclusion, transcription exerts a dual role on genome stability. On the one hand, transcription and de novo RNA synthesis associated with DNA repair and chromatin remodelling processes preserve genome integrity and ensure proper gene functionality. On the other hand, transcription can directly or indirectly lead to genome instability through mechanisms such as transcription-replication conflicts or formation of noncanonical DNA and DNA:RNA hybrid structures (Fig. 1). The equilibrium between these opposing events is critical for genome integrity and requires a fine orchestration of factors acting in transcription, DNA replication, recombination and DNA repair. Events altering such subtle interplay can be highly detrimental, as observed in cancer, ageing or neurodegenerative disorders.

The aim of the present Special Issue is to collect reviews by experts in the field depicting how transcription can play essential roles in preserving genome stability. In particular, Ouyang compares transcription to a dual-edged sword in genome maintenance [[20]]. Azzalin describes the dangerous role of the long noncoding RNA TERRA in telomere maintenance [[21]]. The cellular requirement to quickly recover transcription after genotoxic stress is described by Ogi and colleagues with a Graphical Review focussing on transcription-coupled nucleotide excision repair [[22]], whereas Yang and Lan describe transcription-coupled homologous recombination repair [[23]]. Francia and colleagues depict the intricate interplay occurring at the site of DNA breaks among DNA repair factors, transcription machinery, local synthesis of noncoding RNAs and chromatin modifications [[24]]. The pivotal role of the cohesin complex in the delicate equilibrium required between transcription, chromatin remodelling and maintenance of genome stability is addressed by Di Nardo and Musio [[25]], while Cooke, Herman and Sivaramakrishnan describe the causes and consequences of transcription-replication collisions, which can be a major source of genome instability [[26]]. The physiological relevance of R-loop structures and the factors involved in their resolution has been addressed by Stratigi, Siametis and Garinis [[27]]. Frobel and Hänsel-Hertsch hypothesise that the age-related decline of sirtuin activity may promote the persistent presence of acetylated—and thus less active—helicases at G4 and R-loop structures, thereby promoting DNA damage accumulation and genome instability [[28]]. In addition, Donnio and Giglia-Mari detail current knowledge about the mechanisms allowing faithful transcription after DNA repair [[29]]. Overall, we hope that readers will find this collection of articles instructive and useful for their own studies, with the desire of providing new perspectives to genomic instability disorders.