Surviving chromosome replication: The many roles of the S-phase checkpoint pathway

Karim Labib, Giacomo de Piccoli

    Research output: Contribution to journalArticle

    67 Citations (Scopus)

    Abstract

    Checkpoints were originally identified as signalling pathways that delay mitosis in response to DNA damage or defects in chromosome replication, allowing time for DNA repair to occur. The ATR (ataxia- and rad-related) and ATM (ataxia-mutated) protein kinases are recruited to defective replication forks or to sites of DNA damage, and are thought to initiate the DNA damage response in all eukaryotes. In addition to delaying cell cycle progression, however, the S-phase checkpoint pathway also controls chromosome replication and DNA repair pathways in a highly complex fashion, in order to preserve genome integrity. Much of our understanding of this regulation has come from studies of yeasts, in which the best-characterized targets are the stimulation of ribonucleotide reductase activity by multiple mechanisms, and the inhibition of new initiation events at later origins of DNA replication. In addition, however, the S-phase checkpoint also plays a more enigmatic and apparently critical role in preserving the functional integrity of defective replication forks, by mechanisms that are still understood poorly. This review considers some of the key experiments that have led to our current understanding of this highly complex pathway.
    Original languageEnglish
    Pages (from-to)3554-3561
    Number of pages8
    JournalPhilosophical Transactions of the Royal Society B - Biological Sciences
    Volume366
    Issue number1584
    DOIs
    Publication statusPublished - 27 Dec 2011

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