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Interplay of replication checkpoints and repair proteins at stalled replication forks

FIRC Institute of Molecular Oncology Foundation, Via Adamello 16, 20139 Milan, Italy.
DNA Repair (Impact Factor: 3.36). 08/2007; 6(7):994-1003. DOI: 10.1016/j.dnarep.2007.02.018
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ABSTRACT DNA replication is an essential process that occurs in all growing cells and needs to be tightly regulated in order to preserve genetic integrity. Eukaryotic cells have developed multiple mechanisms to ensure the fidelity of replication and to coordinate the progression of replication forks. Replication is often impeded by DNA damage or replication blocks, and the resulting stalled replication forks are sensed and protected by specialized surveillance mechanisms called checkpoints. The replication checkpoint plays an essential role in preventing the breakdown of stalled replication forks and the accumulation of DNA structures that enhance recombination and chromosomal rearrangements that ultimately lead to genomic instability and cancer development. In addition, the replication checkpoint is thought to assist and coordinate replication fork restart processes by controlling DNA repair pathways, regulating chromatin structure, promoting the recruitment of proteins to sites of damage, and controlling cell cycle progression. In this review we focus mainly on the results obtained in budding yeast to discuss on the multiple roles of checkpoints in maintaining fork integrity and on the enzymatic activities that cooperate with the checkpoint pathway to promote fork resumption and repair of DNA lesions thereby contributing to genome integrity.

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Available from: Dana Branzei, Sep 22, 2014
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    • "repair machinery (Weinert and Hartwell 1988; Branzei and Foiani 2007). Furthermore, recent studies have shown that checkpoint proteins also play a role in morphogenesis in S. cerevisiae and Candida albicans (Jiang and Kang 2003; Enserink et al. 2006; Smolka et al. 2006; Shi et al. 2007) in addition to their role in cell cycle arrest and DNA repair (Wang 2009). "
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    ABSTRACT: In Saccharomyces cerevisiae, replication stress induced by hydroxyurea (HU) and methyl methanesulfonate (MMS) activates DNA integrity checkpoints; in checkpoint-defective yeast strains, HU treatment also induces morphological aberrations. We find that the sphingolipid pathway gene ISC1, the product of which catalyzes the generation of bioactive ceramides from complex sphingolipids, plays a novel role in determining cellular morphology following HU/MMS treatment. HU-treated isc1Δ cells display morphological aberrations, cell-wall defects, and defects in actin depolymerization. Swe1, a morphogenesis checkpoint regulator, and the cell cycle regulator Cdk1 play key roles in these morphological defects of isc1Δ cells. A genetic approach reveals that ISC1 interacts with other checkpoint proteins to control cell morphology. That is, yeast carrying deletions of both ISC1 and a replication checkpoint mediator gene including MRC1, TOF1, or CSM3 display basal morphological defects, which increase following HU treatment. Interestingly, strains with deletions of both ISC1 and the DNA damage checkpoint mediator gene RAD9 display reduced morphological aberrations irrespective of HU treatment, suggesting a role for RAD9 in determining the morphology of isc1Δ cells. Mechanistically, the checkpoint regulator Rad53 partially influences isc1Δ cell morphology in a dosage-dependent manner.
    Genetics 08/2011; 189(2):533-47. DOI:10.1534/genetics.111.132092 · 4.87 Impact Factor
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    • "Moreover, there are factors associated with the repolisome known as the replication fork progression complex which serves to monitor the 'traffic' ahead of the DNA replication fork and mediate a stable and appropriate delay in the fork progression (presumably until the barrier is removed) and the so called 'sweepase' (for example, see Ivessa et al., 2003) which functions to remove barriers, such as RNA polymerases, to prevent them triggering a barrier response in the replisome thereby minimises the chance of a potential fork collapse scenario. This chapter will not review the function of these anti-collapse and fork stabilisation mechanisms, or their link to the cellular checkpoint systems and the reader is directed to a number of other excellent reviews which cover these subjects in more detail (Bartek et al., 2004; Branzei & Foiani, 2007a; 2007b; 2009; 2010; Grallert & Boye, 2008; Harrison & Haber, 2006; Lambert et al., 2007; Labib, 2008; Labib & Hodgson, 2007; McFarlane et al., 2010; Paulsen & Cimprich, 2007; Putnam et al., 2009b; Yao & O'Donnell, 2009). "
    DNA Replication-Current Advances, 08/2011; , ISBN: 978-953-307-593-8
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    • "In addition to a cell-cycle delay defect, checkpoint mutants display increased gross chromosomal rearrangements (Myung et al., 2001; Casper et al., 2002) and, in metazoa, developmental defects (O'Driscoll et al., 2003). The DNA damage responses dependent on the DNA structure checkpoint pathways underpin genome stability (Myung et al., 2001; reviewed in Lambert and Carr, 2005; O'Driscoll and Jeggo, 2003; Branzei and Foiani, 2007). Two large evolutionarily conserved PI3-like protein kinases (Abraham, 2001) are essential for the detection of aberrant DNA structures. "
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    ABSTRACT: When inappropriate DNA structures arise, they are sensed by DNA structure-dependent checkpoint pathways and subsequently repaired. Recruitment of checkpoint proteins to such structures precedes recruitment of proteins involved in DNA metabolism. Thus, checkpoints can regulate DNA metabolism. We show that fission yeast Rad9, a 9-1-1 heterotrimeric checkpoint-clamp component, is phosphorylated by Hsk1(Cdc7), the Schizosaccharomyces pombe Dbf4-dependent kinase (DDK) homolog, in response to replication-induced DNA damage. Phosphorylation of Rad9 disrupts its interaction with replication protein A (RPA) and is dependent on 9-1-1 chromatin loading, the Rad9-associated protein Rad4/Cut5(TopBP1), and prior phosphorylation by Rad3(ATR). rad9 mutants defective in DDK phosphorylation show wild-type checkpoint responses but abnormal DNA repair protein foci and decreased viability after replication stress. We propose that Rad9 phosphorylation by DDK releases Rad9 from DNA damage sites to facilitate DNA repair.
    Molecular cell 11/2010; 40(4):606-18. DOI:10.1016/j.molcel.2010.10.026 · 14.46 Impact Factor
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