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Maintaining genetic fidelity is paramount for all living organisms. The process of replicating DNA is especially dangerous for cells. Not only must the genetic sequence be replicated precisely by the replicative polymerases, but stalled replication forks and single-stranded DNA present at the forks increase risks of chromosome breakage leading to rearrangements. Also, once the cell commits itself to the replication process it has to be fully completed before chromosomes can be disentangled and condensed prior to their proper segregation in the subsequent mitosis. Many processes have evolved that ensure the precision and stability of the replication process; helicases remove bound proteins in front of the fork, topoisomerases ensure that topological entanglements generated during replication are resolved; checkpoint activation in response to stalled replication forks controls an array of molecular responses, repair polymerases and proteins to be recruited to stalled replication forks to allow replication restart; moreover, origin firing is controlled such that firing of origins is delayed in response to the replication checkpoint and dormant origins can be activated if replication is not completed. It is at first hand therefore surprising that at specific loci in the genome, molecular mechanisms exist where deliberate pausing or termination of the replication fork occur. This wonder is further confounded by the fact that several studies have shown that these replication barriers cause genetic instability (see MacFarlane, Al-Zeer and Dalgaard, Chapter 16). What the evolutionary benefits of these replication barriers might be remains a major question. More and more evidence is accumulating that indicates many replication barriers have opposing effects on genome stability; on one hand they promote genetic stability though a controlled stalling of the replication fork at specific sites or situations, however, in doing so they potentially cause fork collapse and genetic instability. In many cases these barriers “coordinate” transcription and replication, preventing collisions between the two types of enzymatic complexes, suggesting that such collisions are more detrimental to the stability of the genome than the instability induced by stalling at a replication barrier (references are given in the main text). Thus, one might argue that most replication barriers evolved to promote genetic stability while allowing “controlled” genetic instability, although other functions of replication barriers are also |
