January 2019: when Transcription Meets Replication

Conflicting activities necessary for the expression, the maintenance and the propagation of genomes need to be coordinated. Just like one's liberty to swing fists ends where another's nose begins, coordination is achieved through a tight control of where and when directly opposed activities take place. In a study published recently in eLife, researchers from the Libri team are now showing that replication factors generally "protect" sites where replication initiates by terminating incoming transcription, and that the low levels of transcription that enter origins of replication affect their firing efficiency.

Legend: Replication origins are “protected” in yeast from incoming RNA polymerases (blue) whose transcription is terminated by a roadblock mechanism. The low levels of transcription that enter origins affect their function.

The notion of transcription-replication conflicts comes from the realization that both DNA and RNA polymerases read DNA filaments 3' to 5'. RNA polymerases transcribing genomes that concomitantly undergo replication may therefore collide with replisomes. Such collisions may result in DNA breakage and should be avoided. Also, translocation may interfere with the binding of replication factors to DNA, which may antagonize the initiation of replication and should also be prevented. As transiently shutting-down all transcription would likely challenge the general fitness of the organism, it has been proposed that cells evolved pathways either to mediate transcription-replication conflicts, and/or to mutually exclude transcription and replication activities.

Replication initiates on genomes from highly specialized zones coined "replication origins" that are generally excluded from genes. However, a lot of transcription occurs outside of genes (the so-called pervasive transcription) that might invade replication origins. Acting as a mechanism counteracting pervasive transcription, DNA-bound proteins can "roadblock" RNAPIIs, i.e. physically impede their progression. The study by Candelli et al. reports the genome-wide impact of pervasive transcription on the function of yeast replication origins. Their results show that, once RNAPIIs reach origin borders, replication factors bound to chromatin roadblock them, generally "protecting" regions where replication originates from invading transcription. Importantly, however, protection is not watertight, which allows some transcription to pass by. This low level of transcription is important for origin function, which is therefore one of the factors that define when and how efficiently origins fire.

Candelli et al. therefore propose that, at the molecular level, spreading your beach towel on the sand reduces the chance of other vacationers sit immediately next to you. Still, it does not prevent their kids to invade your towel-defined space, which will definitely interfere with the enjoyment of your sunbathing time.

To know more: When Transcription Meets Replication
Candelli, T., Gros, J. and Libri, D. Pervasive transcription fine-tunes replication origin activity. eLife. 2018 Dec 17;7.
Contact. Julien Gros julien.gros(at)ijm.fr and Domenico Libri domenico.libri(at)ijm.fr

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