Abstract
Replication forks encounter obstacles that must be repaired or bypassed to complete chromosome duplication before cell division. Proteomic analysis of replication forks suggests that the checkpoint and repair machinery travels with unperturbed forks, implying that they are poised to respond to stalling and collapse. However, impaired fork progression still generates aberrations, including repeat copy number instability and chromosome rearrangements. Deregulated origin firing also causes fork instability if a newer fork collides with an older one, generating double-strand breaks (DSBs) and partially rereplicated DNA. Current evidence suggests that multiple mechanisms are used to repair rereplication damage, yet these can have deleterious consequences for genome integrity.
Highlights
Complete and accurate duplication of DNA at each S phase is required to maintain genome integrity in dividing cells
Recent studies in yeast and Drosophila have permitted the analysis of rereplication at specific genomic sites and demonstrated directly that rereplication can lead to fork collision and formation of double-strand breaks (DSBs)
There are parallels between these fork collision events and fork stalling during normal DNA replication, such as the involvement of DNA damage signaling pathways, the extent to which repair mechanisms are shared remains to be determined
Summary
In G1 of the cell cycle, origins of replication are bound by the prereplication complex (pre-RC). Of the pre-IC and origin melting are accompanied by activation of the CMG helicase and polymerase recruitment This requires that the MCM2–7 complex transitions from encircling dsDNA as part of the pre-RC to ssDNA as part of the replication fork. An interesting finding emerging from fork component characterization is that several checkpoint and repair proteins are detected at replication forks in the absence of damaging conditions (Sirbu et al 2011, 2013; Alabert et al 2014) These results raise the interesting possibility that forks are poised to deal with stalling throughout S phase. This latter explanation is made less likely by the expectation that the proportional contribution of such forks would to be low
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