Cdc7 kinase mediates Claspin phosphorylation in DNA replication checkpoint

Kim, J M; Kakusho, Naoko; Yamada, Masayuki; Kanoh, Yutaka; Takemoto, Naofumi; Masai, Hisao

doi:10.1038/sj.onc.1210994

Cited by 87 publications

(118 citation statements)

References 51 publications

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“…4A). The decreased Chk1 levels in Cdc7-depleted cells might be due to the reduced S phase fraction in these cells (34), but changes in cell-cycle distribution can not explain the reduction of Cdc7 in Chk1-depleted cells, because Cdc7 levels are stable throughout the cell cycle (35). Cdc7 might become down-regulated to counteract some of the increased origin firing in Chk1-depleted cells.…”

Section: Discussionmentioning

confidence: 99%

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Chk1 promotes replication fork progression by controlling replication initiation

Petermann

Woodcock

Helleday

2010

Proc. Natl. Acad. Sci. U.S.A.

259

252

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DNA replication starts at initiation sites termed replication origins. Metazoan cells contain many more potential origins than are activated (fired) during each S phase. Origin activation is controlled by the ATR checkpoint kinase and its downstream effector kinase Chk1, which suppresses origin firing in response to replication blocks and during normal S phase by inhibiting the cyclin-dependent kinase Cdk2. In addition to increased origin activation, cells deficient in Chk1 activity display reduced rates of replication fork progression. Here we investigate the causal relationship between increased origin firing and reduced replication fork progression. We use the Cdk inhibitor roscovitine or RNAi depletion of Cdc7 to inhibit origin firing in Chk1-inhibited or RNAi-depleted cells. We report that Cdk inhibition and depletion of Cdc7 can alleviate the slow replication fork speeds in Chk1-deficient cells. Our data suggest that increased replication initiation leads to slow replication fork progression and that Chk1 promotes replication fork progression during normal S phase by controlling replication origin activity.

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Section: Discussionmentioning

confidence: 99%

“…4). In addition to origin firing, Cdc7 has been implicated in the DNA damage response; it interacts with and phosphorylates Claspin, thus promoting Chk1 phosphorylation (34). As a mediator of Chk1 activation, Cdc7 could be expected to be required for normal replication fork rates like ATR and Claspin.…”

Section: Discussionmentioning

confidence: 99%

Chk1 promotes replication fork progression by controlling replication initiation

Petermann

Woodcock

Helleday

2010

Proc. Natl. Acad. Sci. U.S.A.

259

252

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“…Apoptotic cancer cell death in response to Cdc7 inhibition is p53-independent and, at least in some cancer cell lines, is mediated via the stress-activated protein p38MAPK in an ATM-and Rad3-related (ATR)-dependent manner [132]. Interestingly, in addition to its function in origin firing, Cdc7 kinase has been shown to play an essential role in mediating the ATR-Chk1 pathway by phosphorylating the Chk1 activator Claspin [133,134]. Hence, the dual effect of Cdc7 inhibitors on DNA replication and DNA damage response pathways may further potentiate cancer cell killing.…”

Section: The Dna Replication Initiation Machinery-a Promising Anti-camentioning

confidence: 99%

The cell cycle and cancer

Williams

Stoeber

2011

The Journal of Pathology

579

406

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Deregulation of the cell cycle underlies the aberrant cell proliferation that characterizes cancer and loss of cell cycle checkpoint control promotes genetic instability. During the past two decades, cancer genetics has shown that hyperactivating mutations in growth signalling networks, coupled to loss of function of tumour suppressor proteins, drives oncogenic proliferation. Gene expression profiling of these complex and redundant mitogenic pathways to identify prognostic and predictive signatures and their therapeutic targeting has, however, proved challenging. The cell cycle machinery, which acts as an integration point for information transduced through upstream signalling networks, represents an alternative target for diagnostic and therapeutic interventions. Analysis of the DNA replication initiation machinery and mitotic engine proteins in human tissues is now leading to the identification of novel biomarkers for cancer detection and prognostication, and is providing target validation for cell cycle-directed therapies.

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“…10,11 Because Cdc7 overexpression promotes proliferation and survival of certain tumor cells, knockdown of Cdc7 by siRNA has led to p53-independent apoptosis in cancer cell lines. 12,13 Tumor cells with the often impaired S-phase checkpoints progress to mitosis without DNA repair. Meanwhile, upon Cdc7 depletion, normal cells are able to arrest in the G1 phase of the cell cycle and resume normal divisions once an initiation process is restored.…”

mentioning

confidence: 99%

Azaindole-Based Inhibitors of Cdc7 Kinase: Impact of the Pre-DFG Residue, Val 195

Tong

Stewart

Florjancic

et al. 2013

ACS Med. Chem. Lett.

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To investigate the role played by the unique pre-DFG residue Val 195 of Cdc7 kinase on the potency of azaindole-chloropyridines (1), a series of novel analogues with various chloro replacements were synthesized and evaluated for their inhibitory activity against Cdc7. X-ray cocrystallization using a surrogate protein, GSK3β, and modeling studies confirmed the azaindole motif as the hinge binder. Weaker hydrophobic interactions with Met 134 and Val 195 by certain chloro replacements (e.g., H, methyl) led to reduced Cdc7 inhibition. Meanwhile, data from other replacements (e.g., F, O) indicated that loss of such hydrophobic interaction could be compensated by enhanced hydrogen bonding to Lys 90. Our findings not only provide an in-depth understanding of the pre-DFG residue as another viable position impacting kinase inhibition, they also expand the existing knowledge of ligand-Cdc7 binding.

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Cdc7 kinase mediates Claspin phosphorylation in DNA replication checkpoint

Cited by 87 publications

References 51 publications

Chk1 promotes replication fork progression by controlling replication initiation

Chk1 promotes replication fork progression by controlling replication initiation

The cell cycle and cancer

Azaindole-Based Inhibitors of Cdc7 Kinase: Impact of the Pre-DFG Residue, Val 195

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