DNA damage checkpoints and DNA replication controls in Saccharomyces cerevisiae

Foiani, Marco; Pellicioli, Achille; Lopes, Massimo; Lucca, Chiara; Ferrari, Marina G.; Liberi, Giordano; Muzi-Falconi, Marco; Plevani, Paolo

doi:10.1016/s0027-5107(00)00049-x

Cited by 111 publications

(89 citation statements)

References 59 publications

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“…In budding yeast, the DNA replication checkpoint arrests cells in a metaphase-like state with spindle formation rather than in interphase (29), as in most other eukaryotes, including fission yeast. Consistent with this observation, Mad1p and Mad2p were recently shown to be required for the DNA replication checkpoint in budding yeast (30).…”

Section: Figmentioning

confidence: 99%

DNA Replication Checkpoint Control Mediated by the Spindle Checkpoint Protein Mad2p in Fission Yeast

Sugimoto

Murakami

Tonami

et al. 2004

Journal of Biological Chemistry

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The relationship between the DNA replication and spindle checkpoints of the cell cycle is unclear, given that in most eukaryotes, spindle formation occurs only after DNA replication is complete. Fission yeast rad3 mutant cells, which are deficient in DNA replication checkpoint function, enter, progress through, and exit mitosis even when DNA replication is blocked. In contrast, the entry of cds1 mutant cells into mitosis is delayed by several hours when DNA replication is inhibited. We show here that this delay in mitotic entry in cds1 cells is due in part to activation of the spindle checkpoint protein Mad2p. In the presence of the DNA replication inhibitor hydroxyurea (HU), cds1 mad2 cells entered and progressed through mitosis earlier than did cds1 cells. Overexpression of Mad2p or inactivation of Slp1p, a regulator of the anaphase-promoting complex, also rescued the checkpoint defect of HU-treated rad3 cells. Rad3p was shown to be involved in the physical interaction between Mad2p and Slp1p in the presence of HU. These results suggested that Mad2p and Slp1p act downstream of Rad3p in the DNA replication checkpoint and that Mad2p is required for the DNA replication checkpoint when Cds1p is compromised.

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Section: Figmentioning

confidence: 99%

DNA Replication Checkpoint Control Mediated by the Spindle Checkpoint Protein Mad2p in Fission Yeast

Sugimoto

Murakami

Tonami

et al. 2004

Journal of Biological Chemistry

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“…Hence, cells to maintain the integrity of replicating chromosomes have to coordinate highly DNA replication with DNA repair and recombination. Eukaryotic cells have developed a sophisticated control mechanism, known as replication checkpoint (Foiani et al, 2000;Boddy and Russell, 2001;Osborn et al, 2002), entirely devoted to coordinate replication with repair, recombination, transcription and cell cycle progression. A failure to activate or transduce the replication checkpoint response inevitably results in genome instability and cancer (Shiloh, 2001).…”

Section: Introductionmentioning

confidence: 99%

“…In yeast, the replication checkpoint is mediated by the Mec1 (ATM/ATR orthologue) and Rad53 (Chk2 orthologue) kinases (Foiani et al, 2000) that actively control the integrity of replicating chromosomes in response to replication pausing or intra-S DNA damage (Lopes et al, 2001;Tercero and Diffley, 2001;Sogo et al, 2002). rad53 cells exposed to hydroxyurea (HU)-induced replication blocks progressively accumulate abnormal replication structures characterized by extensive singlestranded DNA (ss-DNA) regions at the forks.…”

Section: Introductionmentioning

confidence: 99%

Checkpoint-mediated control of replisome–fork association and signalling in response to replication pausing

et al. 2003

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The replication checkpoint controls the integrity of replicating chromosomes by stabilizing stalled forks, thus preventing the accumulation of abnormal replication and recombination intermediates that contribute to genome instability. Checkpoint-defective cells are susceptible to rearrangements at chromosome fragile sites when replication pauses, and certain human cancer prone diseases suffer checkpoint abnormalities. It is unclear as to how the checkpoint stabilizes stalled forks and how cells sense replication blocks. We have analysed the checkpoint contribution in controlling replisome-fork association when replication pauses. We show that in yeast wild-type cells, stalled forks exhibit stable replisome complexes and the checkpoint sensors Ddc1 and Ddc2, thus activating Rad53 checkpoint kinase. Ddc1/Ddc2 recruitment on stalled forks and Rad53 activation are influenced by the single-strand-binding protein replication factor A (RFA). rad53 forks exhibit a defective association with DNA polymerases a, e and d. Further, in rad53 mutants, stalled forks progressively generate abnormal structures that turn into checkpoint signals by accumulating RFA, Ddc1 and Ddc2. We suggest that, following replication blocks, checkpoint activation mediated by RFA-ssDNA filaments stabilizes stalled forks by controlling replisome-fork association, thus preventing unscheduled recruitment of recombination enzymes that could otherwise cause the pathological processing of the forks.

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“…10). Rad53 kinase activation is required for arrest at all stages of the cell cycle (G 1 /S, intra-S and G 2 /M checkpoints) depending on where the DNA damage occurs and for a replication checkpoint that monitors the progress of DNA replication (11,12).…”

mentioning

confidence: 99%

“…This facilitates a rapid response to DNA replication blocks that includes stabilization of stalled replication forks, inhibition of late origin firing, and prevention of S/M spindle elongation (reviewed in Ref. 10). In response to either of these pathways, Rad53 is activated through phosphorylation in a Mec1-dependent manner and then integrates these signals to activate effectors.…”

mentioning

confidence: 99%

Rad53 Kinase Activation-independent Replication Checkpoint Function of the N-terminal Forkhead-associated (FHA1) Domain

Pike

Tenis

Heierhorst

2004

Journal of Biological Chemistry

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Saccharomyces cerevisiae Rad53 has crucial functions in many aspects of the cellular response to DNA damage and replication blocks. To coordinate these diverse roles, Rad53 has two forkhead-associated (FHA) phosphothreonine-binding domains in addition to a kinase domain. Here, we show that the conserved N-terminal FHA1 domain is essential for the function of Rad53 to prevent the firing of late replication origins in response to replication blocks. However, the FHA1 domain is not required for Rad53 activation during S phase, and as a consequence of defective downstream signaling, Rad53 containing an inactive FHA1 domain is hyperphosphorylated in response to replication blocks. The FHA1 mutation dramatically hypersensitizes strains with defects in the cell cycle-wide checkpoint pathways (rad9⌬ and rad17⌬) to DNA damage, but it is largely epistatic with defects in the replication checkpoint (mrc1⌬). Altogether, our data indicate that the FHA1 domain links activated Rad53 to downstream effectors in the replication checkpoint. The results reveal an important mechanistic difference to the homologous Schizosaccharomyces pombe FHA domain that is required for Mrc1-dependent activation of the corresponding Cds1 kinase. Surprisingly, despite the severely impaired replication checkpoint and also G 2 /M checkpoint functions, the FHA1 mutation by itself leads to only moderate viability defects in response to DNA damage, highlighting the importance of functionally redundant pathways.

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DNA damage checkpoints and DNA replication controls in Saccharomyces cerevisiae

Cited by 111 publications

References 59 publications

DNA Replication Checkpoint Control Mediated by the Spindle Checkpoint Protein Mad2p in Fission Yeast

DNA Replication Checkpoint Control Mediated by the Spindle Checkpoint Protein Mad2p in Fission Yeast

Checkpoint-mediated control of replisome–fork association and signalling in response to replication pausing

Rad53 Kinase Activation-independent Replication Checkpoint Function of the N-terminal Forkhead-associated (FHA1) Domain

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