Abstract
Transcription-replication interactions occur when DNA replication encounters genomic regions undergoing transcription. Both replication and transcription are essential for life and use the same DNA template making conflicts unavoidable. R-loops, DNA supercoiling, DNA secondary structure, and chromatin-binding proteins are all potential obstacles for processive replication or transcription and pose an even more potent threat to genome integrity when these processes co-occur. It is critical to maintaining high fidelity and processivity of transcription and replication while navigating through a complex chromatin environment, highlighting the importance of defining cellular pathways regulating transcription-replication interaction formation, evasion, and resolution. Here we discuss how transcription influences replication fork stability, and the safeguards that have evolved to navigate transcription-replication interactions and maintain genome integrity in mammalian cells.
Highlights
Studies in mammalian cells showed that transcriptionassociated recombination (TAR) was dependent on S phase, further supporting the model that transcription stalled replication fork progression and stimulated recombinational repair and transcription is a major source of endogenous replication stress and DNA damage [3]
TAR can arise from several processes including altering the expression of genes that are required for genome maintenance, the opening of heterochromatin, formation of co-transcriptional structures such as R-loops, or TOP2B cleavage [4,5]
The ataxia-telangiectasia mutated (ATM) kinase is recruited to doublestranded breaks (DSBs) while ATR is recruited to single-stranded DNA that could result from events such as stalled replication forks or resected DSBs [155]
Summary
Studies in bacteria demonstrated that the direction of transcription relative to replication at TRIs has a profound effect on genome instability. Another study was performed investigating convergent TRIs between RNAP and replication forks in E. coli [11]. Replication forks encountering an RNAP moving in the same direction are associated with nonsynonymous mutations, though the effects were less pronounced than convergent collisions [12]. Codirectional TRIs only have modest effects on replication fork progression compared to head-on events [15]. E. coli found that a replication fork approaching RNAP moving codirectionally uses an mRNA transcript to continue replication after the RNAP has been displaced.
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