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Cell Mol Life Sci. 2017 Jul;74(13):2361-2380. doi: 10.1007/s00018-017-2474-4. Epub 2017 Feb 20.

S-phase checkpoint regulations that preserve replication and chromosome integrity upon dNTP depletion.

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Fondazione Istituto FIRC di Oncologia Molecolare (IFOM), Via Adamello 16, 20139, Milan, Italy.
Dipartimento di Oncologia ed Emato-Oncologia, Università degli Studi di Milano, Milan, Italy.
Fondazione Istituto FIRC di Oncologia Molecolare (IFOM), Via Adamello 16, 20139, Milan, Italy.


DNA replication stress, an important source of genomic instability, arises upon different types of DNA replication perturbations, including those that stall replication fork progression. Inhibitors of the cellular pool of deoxynucleotide triphosphates (dNTPs) slow down DNA synthesis throughout the genome. Following depletion of dNTPs, the highly conserved replication checkpoint kinase pathway, also known as the S-phase checkpoint, preserves the functionality and structure of stalled DNA replication forks and prevents chromosome fragmentation. The underlying mechanisms involve pathways extrinsic to replication forks, such as those involving regulation of the ribonucleotide reductase activity, the temporal program of origin firing, and cell cycle transitions. In addition, the S-phase checkpoint modulates the function of replisome components to promote replication integrity. This review summarizes the various functions of the replication checkpoint in promoting replication fork stability and genome integrity in the face of replication stress caused by dNTP depletion.


ATR/Mec1/Rad3; Chromosome fragility; Fork remodeling; Helicases; Nucleases; Rad53/CHK1/Cds1; Stalled replication forks

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