The induction of ssDNA foci is a secondaryevent resulting from cellular responses to different types of clastogens.First, the initial DSB is processed by unidirectional to exonuclease digestion of one Targetmol’s Furosemide strand of each end to produce rather long overhanging ssDNA tails. The number of ssDNA foci in meiotic prophase cells was severalfold lower than the expected frequency of crossingover events. Cells responding with the slow system, which may involve homologous recombination, are repaired within hr.The bulk of DSB repair is completed at hr after irradiation, when the max imum number of ssDNA foci is observed.Indeed, measurements on extended chromatin fibers suggest that some filaments may contain up to kb of ssDNA.In addition, damagesensitive regions are nonrandomly distributed in the highly substructured mammalian cell nucleus.For example, DNA lesions recognized by singlestrand specific S nuclease are clustered in the genome. The extent and genomic distribution of DNA damage seems to depend on higherorder chromatin structure. One possible explanation for such a commitment may be the cellcycle stage at which the cell experiences DNA damage.This work was supported by Grants Hay from the Deutsche Forschungsgemeinschaft and RGM from the National Institutes of Health. Maser, R. S, Monsen, K. J, Nelms, B. E. Petrin i, J. H. J. Mol. Cell. Biol, rebmetpe Snotseugybded aonlwoD The user has requested enhancement of the downloaded file.Replication forks stall or collapse at DNA lesions or problematic genomic regions, and these events have often been associated with recombination and chromosomal rearrangements.Stalled forks generate singlestranded DNA that activates the replication checkpoint, which in turn functions to protect the stability of the fork until the replication can resume.Recombinationmediated and damagebypass processes are the main mechanisms responsible for replication restart.New ndings have helped to unmask the molecular mechanisms that sense replication stress, control the stability of replication forks, and regulate the mechanisms that promote replication restart, thereby giving us a better understanding of how genome integrity is preserved during replication.DNA replication represents a dangerous moment in the life of the cell as endogenous and exogenous events challenge genome integrity by interfering with the progression, stability and restart of the replication fork.To deal with this responsibility, replication forks are endowed with an extraordinary potential to coordinate fork stalling with fork resumption processes.Failure to protect stalled forks or to process the replication fork appropriately for replication restart results in the accumulation of mutations and genomic aberrations.Indeed, a variety of human genetic syndromes that lead to cancer predisposition are caused by mutations in genes that protect the genome integrity during chromosome replication.In this review we will comment on the recent ndings that helped to elucidate how stalled forks signal to the replication checkpoint, how the checkpoint mechanisms contribute to the stability of the fork, the mechanisms that assist and coordinate fork restart, and the enzymatic activities that process stalled or collapsed forks.These chromosomal loci are known as fragile sites and induce fork pausing, which is often associated with chromosome breakage and genomic rearrangements. Fork pausing can also be caused by intraS DNA damage through several mechanisms: by causing uncoupling between the replisome and the helicase at the fork; by uncoupling the leading and lagging strand synthesis; or by blocking the replicative helicase progression and therefore inhibiting template unwinding.