scholarly journals SCFβTrCP-Mediated Degradation of Claspin Regulates Recovery from the DNA Replication Checkpoint Response

2006 ◽  
Vol 23 (3) ◽  
pp. 319-329 ◽  
Author(s):  
Angelo Peschiaroli ◽  
N. Valerio Dorrello ◽  
Daniele Guardavaccaro ◽  
Monica Venere ◽  
Thanos Halazonetis ◽  
...  
Nature ◽  
2001 ◽  
Vol 412 (6846) ◽  
pp. 557-561 ◽  
Author(s):  
Massimo Lopes ◽  
Cecilia Cotta-Ramusino ◽  
Achille Pellicioli ◽  
Giordano Liberi ◽  
Paolo Plevani ◽  
...  

DNA Repair ◽  
2011 ◽  
Vol 10 (2) ◽  
pp. 210-224 ◽  
Author(s):  
Susanne M. Germann ◽  
Vibe H. Oestergaard ◽  
Caroline Haas ◽  
Pauline Salis ◽  
Akira Motegi ◽  
...  

2000 ◽  
Vol 14 (1) ◽  
pp. 81-96 ◽  
Author(s):  
Christian Frei ◽  
Susan M. Gasser

We have examined the cellular function of Sgs1p, a nonessential yeast DNA helicase, homologs of which are implicated in two highly debilitating hereditary human diseases (Werner's and Bloom's syndromes). We show that Sgs1p is an integral component of the S-phase checkpoint response in yeast, which arrests cells due to DNA damage or blocked fork progression during DNA replication. DNA polε and Sgs1p are found in the same epistasis group and act upstream of Rad53p to signal cell cycle arrest when DNA replication is perturbed. Sgs1p is tightly regulated through the cell cycle, accumulates in S phase and colocalizes with Rad53p in S-phase-specific foci, even in the absence of fork arrest. The association of Rad53p with a chromatin subfraction is Sgs1p dependent, suggesting an important role for the helicase in the signal-transducing pathway that monitors replication fork progression.


2015 ◽  
Vol 35 (12) ◽  
pp. 2131-2143 ◽  
Author(s):  
Feng-Ling Tsai ◽  
Sriram Vijayraghavan ◽  
Joseph Prinz ◽  
Heather K. MacAlpine ◽  
David M. MacAlpine ◽  
...  

The DNA replication checkpoint (DRC) monitors and responds to stalled replication forks to prevent genomic instability. How core replication factors integrate into this phosphorylation cascade is incompletely understood. Here, through analysis of a uniquemcmallele targeting a specific ATPase active site (mcm2DENQ), we show that the Mcm2-7 replicative helicase has a novel DRC function as part of the signal transduction cascade. This allele exhibits normal downstream mediator (Mrc1) phosphorylation, implying DRC sensor kinase activation. However, the mutant also exhibits defective effector kinase (Rad53) activation and classic DRC phenotypes. Our previousin vitroanalysis showed that themcm2DENQmutation prevents a specific conformational change in the Mcm2-7 hexamer. We infer that this conformational change is required for its DRC role and propose that it allosterically facilitates Rad53 activation to ensure a replication-specific checkpoint response.


Genetics ◽  
1998 ◽  
Vol 150 (4) ◽  
pp. 1361-1375
Author(s):  
Kristi Chrispell Forbes ◽  
Timothy Humphrey ◽  
Tamar Enoch

Abstract Checkpoints maintain the order of cell-cycle events. At G2/M, a checkpoint blocks mitosis in response to damaged or unreplicated DNA. There are significant differences in the checkpoint responses to damaged DNA and unreplicated DNA, although many of the same genes are involved in both responses. To identify new genes that function specifically in the DNA replication checkpoint pathway, we searched for high-copy suppressors of overproducer of Cdc25p (OPcdc25+), which lacks a DNA replication checkpoint. Two classes of suppressors were isolated. One class includes a new gene encoding a putative DEAD box helicase, suppressor of uncontrolled mitosis (sum3+). This gene negatively regulates the cell-cycle response to stress when overexpressed and restores the checkpoint response by a mechanism that is independent of Cdc2p tyrosine phosphorylation. The second class includes chk1+ and the two Schizosaccharomyces pombe 14-3-3 genes, rad24+ and rad25+, which appear to suppress the checkpoint defect by inhibiting Cdc25p. We show that rad24Δ mutants are defective in the checkpoint response to the DNA replication inhibitor hydroxyurea at 37° and that cds1Δ rad24Δ mutants, like cds1Δ chk1Δ mutants, are entirely checkpoint deficient at 29°. These results suggest that chk1+ and rad24+ may function redundantly with cds1+ in the checkpoint response to unreplicated DNA.


2006 ◽  
Vol 66 (17) ◽  
pp. 8672-8679 ◽  
Author(s):  
Verónica Rodríguez-Bravo ◽  
Sandra Guaita-Esteruelas ◽  
Roger Florensa ◽  
Oriol Bachs ◽  
Neus Agell

2017 ◽  
Vol 114 (19) ◽  
pp. E3766-E3775 ◽  
Author(s):  
Kang Liu ◽  
Fang-Tsyr Lin ◽  
Joshua D. Graves ◽  
Yu-Ju Lee ◽  
Weei-Chin Lin

Accumulating evidence supports the gain-of-function of mutant forms of p53 (mutp53s). However, whether mutp53 directly perturbs the DNA replication checkpoint remains unclear. Previously, we have demonstrated that TopBP1 forms a complex with mutp53s and mediates their gain-of-function through NF-Y and p63/p73. Akt phosphorylates TopBP1 and induces its oligomerization, which inhibits its ATR-activating function. Here we show that various contact and conformational mutp53s bypass Akt to induce TopBP1 oligomerization and attenuate ATR checkpoint response during replication stress. The effect on ATR response caused by mutp53 can be exploited in a synthetic lethality strategy, as depletion of another ATR activator, DNA2, in mutp53-R273H–expressing cancer cells renders cells hypersensitive to cisplatin. Expression of mutp53-R273H also makes cancer cells more sensitive to DNA2 depletion or DNA2 inhibitors. In addition to ATR-activating function during replication stress, TopBP1 interacts with Treslin in a Cdk-dependent manner to initiate DNA replication during normal growth. We find that mutp53 also interferes with TopBP1 replication function. Several contact, but not conformational, mutp53s enhance the interaction between TopBP1 and Treslin and promote DNA replication despite the presence of a Cdk2 inhibitor. Together, these data uncover two distinct mechanisms by which mutp53 enhances DNA replication: (i) Both contact and conformational mutp53s can bind TopBP1 and attenuate the checkpoint response to replication stress, and (ii) during normal growth, contact (but not conformational) mutp53s can override the Cdk2 requirement to promote replication by facilitating the TopBP1/Treslin interaction.


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