The DNA Damage Response during

In the cell life cycle there are some substantial stages including the progressing, stabilising and restarting of the replication fork, where endogenous and exogenous events can confront the genome integrity by stalling the fork. In order to prevent the abnormalities caused by fork stalling, which subsequently makes the chance for cancer to develop, replication forks have a special potential to resume the DNA replication process. In this article the way replication checkpoints participate in processing the mechanisms to stabilise, assist and organise the fork restart is shown, according to recent findings.

Endogenous and exogenous events There are some locations in DNA called fragile sites, where the replication process slows down. The fork pausing in tRNA genes, for example, is associated with either genomic aberrations or DNA damage through mechanisms like uncoupling between strands or helicase being blocked. In case of the replisome remained associated with the fork, some proteins such as the Rrm3 DNA helicase remove the impediments and then the DNA synthesis is restarted.

However, if the replisome dissociates and the fork collapses, it will not be a problem in eukaryotes, as forks coming from adjoining replicons replace the collapsed forks. If the collapse occurs at sub-telomeric regions, where there are no other forks, the forks have to be restarted in order to complete the replication. The Activation of Replication Checkpoints When a fork is stalled, the uncoupling of the MCM helicase and polymerase activities, or between leading and lagging strands, cause the amounts of single-stranded DNA (ssDNA) coated by replication protein A (RPA) to be exposed, which results in checkpoint signalling.

Once ssDNA goes above a certain level, the Mec1/ATR checkpoint kinase, engaged to stalled forks, gets activated and phosphorylates a protein called Mrc1, which, finally, relieves the replication block for fork restarting. However, in some cases, the checkpoint activation is not generated or the signal may be muffled because of either the cells either having lack of replication proteins or checkpoint system, or the segmental chromosome duplications. Stabilisation of stalled forks

In checkpoint mutants, stalled forks break up and accumulate ssDNA molecules, resulted from lagging strand defects and also four-branched molecules, resulted from sister chromatid junctions having run off. After Stabilising, the checkpoints control the replication fork response to DNA damage by preventing the late or inactive origins being fired. However, in cells with faulty checkpoint systems, the unscheduled replicon firing could be the best option to complete replication.

During stabilising the forks, the MCM complex, RPA and Mrc1 phosphorylation are thought to be involved in the stabilising the association of the replisome-fork, which occurs through controlling the activity of recombination enzymes. Restart Mechanisms Recombination-mediated mechanisms, which complete the replication when there are no converging forks or there are double-strand breaks, do not need initiation functions to assist damage bypass mechanisms. These mechanisms contain using specialized polymerases, information from undamaged sister chromatid, or joint structures, to overcome intra-S damage and replication barriers.

Below are two examples: 1. PCNA: a replication fork signal receiver that forms damage-induced mutations and bypass mechanisms to resume the replication. It also accumulates Srs2 in forks to prevent recombination repair from happening during S phase. 2. RecQ helicases: enzymes associated with maintaining genome stability by responding to intra-S damage. Its complex with Top3 (RecQ/Top3) resolves recombination intermediates and contains a DNA-binding protein encoded from RMII gene.

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