Abstract
Transcription–replication conflicts occur when the two critical cellular machineries responsible for gene expression and genome duplication collide with each other on the same genomic location. Although both prokaryotic and eukaryotic cells have evolved multiple mechanisms to coordinate these processes on individual chromosomes, it is now clear that conflicts can arise due to aberrant transcription regulation and premature proliferation, leading to DNA replication stress and genomic instability. As both are considered hallmarks of aging and human diseases such as cancer, understanding the cellular consequences of conflicts is of paramount importance. In this article, we summarize our current knowledge on where and when collisions occur and how these encounters affect the genome and chromatin landscape of cells. Finally, we conclude with the different cellular pathways and multiple mechanisms that cells have put in place at conflict sites to ensure the resolution of conflicts and accurate genome duplication.
Highlights
Transcription and replication are the two major nuclear processes that use large cellular resources to allow gene expression and DNA duplication, respectively
Several gene sets display crucial S-phase-specific functions, for example, replication factors and core histone genes that together allow assembly of the newly synthesized DNA into nucleosomes [2,3], ribosomal RNA genes to provide a continuous supply of ribosomes [4] or other long genes that are initiated in the G1 phase, but completion of their transcription cycle extends into the S-phase [5]
The contribution of the SWI/SNF complex was independently confirmed by the Aguilera lab, showing that the main ATPase BRG1 colocalizes with R-loops and helps in resolving R-loop-mediated transcription–replication conflicts (TRCs) [95]
Summary
Transcription and replication are the two major nuclear processes that use large cellular resources to allow gene expression and DNA duplication, respectively. During the G1phase, transcription may have a more direct role in negotiating TRCs, as it was shown in vitro that intragenic MCM2-7 double-hexamer complexes can be repositioned to the transcription termination site by active “pushing” by RNA polymerase (Figure 1, G1) [18] Whether this redistribution shows the same extent in the context of chromatin in vivo and whether this results in an inactivation of the origin are still open questions, but active transcription clearly has the potential to shape the landscape of replication initiation sites prior to S-phase entry [19,20]. Despite these multiple strategies that cells are equipped with to coordinate the two machineries and prevent TRCs, occasional encounters appear to be inevitable. We will provide an overview of the multiple pathways and partially redundant mechanisms that cells have put in place to process these conflicts, highlighting the importance of conflict resolution towards the overall goal of accurate genome duplication
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