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Regulation and roles of Cdc7 kinase under replicationstressMasayuki Yamadaa, Hisao Masaib & Jiri Bartekac

a Institute of Molecular and Translational Medicine; Faculty of Medicine and Dentistry;Palacky University; Olomouc, Czech Republicb Genome Dynamics Project; Department of Genome Medicine; Tokyo Metropolitan Instituteof Medical Science; Tokyo, Japanc Danish Cancer Society Research Center; Copenhagen, DenmarkPublished online: 19 May 2014.

To cite this article: Masayuki Yamada, Hisao Masai & Jiri Bartek (2014) Regulation and roles of Cdc7 kinase under replicationstress, Cell Cycle, 13:12, 1859-1866, DOI: 10.4161/cc.29251

To link to this article: http://dx.doi.org/10.4161/cc.29251

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cell cycle 13:12, 1859–1866; June 15, 2014; © 2014 Landes Bioscience

PersPective PersPective PersPective

Cdc7 (cell division cycle 7) kinase together with its activation subunit

ASK (also known as Dbf4) play pivotal roles in DNA replication and contribute also to other aspects of DNA metabo-lism such as DNA repair and recombina-tion. While the biological significance of Cdc7 is widely appreciated, the molecu-lar mechanisms through which Cdc7 kinase regulates these various DNA transactions remain largely obscure, including the role of Cdc7-ASK/Dbf4 under replication stress, a condition associated with diverse (patho)physi-ological scenarios. In this review, we first highlight the recent findings on a novel pathway that regulates the sta-bility of the human Cdc7-ASK/Dbf4 complex under replication stress, its interplay with ATR-Chk1 signaling, and significance in the RAD18-depen-dent DNA damage bypass pathway. We also consider Cdc7 function in a broader context, considering both physiological conditions and pathologies associated with enhanced replication stress, par-ticularly oncogenic transformation and tumorigenesis. Furthermore, we inte-grate the emerging evidence and propose a concept of Cdc7-ASK/Dbf4 contribut-ing to genome integrity maintenance, through interplay with RAD18 that can serve as a molecular switch to dictate DNA repair pathway choice. Finally, we discuss the possibility of targeting Cdc7, particularly in the context of the Cdc7/RAD18-dependent translesion synthe-sis, as a potential innovative strategy for treatment of cancer.

Background

The serine–threonine kinase Cdc7 is essential for chromosomal DNA replica-tion in a wide spectrum of species, being conserved from yeast to human.1-4 The activity of the catalytic subunit Cdc7 is positively regulated by a complex forma-tion with its activation subunit, the Dbf4 protein, also known as ASK (activator of S-phase kinase in human).5-10 The Cdc7–ASK/Dbf4 complex is therefore also commonly referred to as the Dbf4-dependent kinase, or DDK in short. DDK regulates the timing of DNA rep-lication origin firing throughout S phase mainly by phosphorylation of MCM proteins, the major components of repli-cative helicase.11-13

When the replication fork stalls, due either to endogenous obstacles or upon exposure of a cell to various genotoxic insults, the DNA replication checkpoint pathway becomes activated14 and sup-presses further origin firing or slows down the fork progression. In budding yeast Saccharomyces cerevisiae, Rad53 checkpoint kinase (an ortholog of human Chk2) directly phosphorylates Dbf4 upon fork stalling to block late origin firing, most likely through downregula-tion of the DDK activity,15-18 although this is not proven yet. Similarly, an in vitro study using Xenopus egg extracts revealed that DDK activity is inhibited upon DNA damage caused by etoposide treatment in an ATR kinase-dependent manner.19 However, later work using a similar experimental system presented a

Regulation and roles of Cdc7 kinase under replication stress

Masayuki Yamada1,*, Hisao Masai2, and Jiri Bartek1,3,*1Institute of Molecular and Translational Medicine; Faculty of Medicine and Dentistry; Palacky University; Olomouc, Czech Republic; 2Genome Dynamics

Project; Department of Genome Medicine; Tokyo Metropolitan Institute of Medical Science; Tokyo, Japan; 3Danish Cancer Society Research Center;

Copenhagen, Denmark

Keywords: Cdc7 kinase, DDK, RAD18, TLS, DNA damage bypass, replication checkpoint, DNA repair pathway choice

Abbreviations: APC/C, anaphase promoting complex/cyclosome; ATR, ataxia telangiectasia and Rad3-related protein; CDK, cyclin-dependent kinase; DDK, Dbf4-dependent kinase; DDR, DNA damage response; FA, Fanconi anemia; HR, homologous recombination; PIP box, PCNA-interacting protein box; RING domain, really interesting new gene domain; TLS, translesion synthesis

Submitted: 05/05/2014

Accepted: 05/15/2014

Published Online: 05/19/2014

http://dx.doi.org/10.4161/cc.29251

*Correspondence to: Jiri Bartek; Email: [email protected]; Masayuki Yamada; Email: [email protected]

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contradictory result, namely preserved DDK activity upon DNA damage.20 It is also controversial whether the human DDK is inactivated under genotoxic stress conditions. Previously, it was reported that Cdc7 kinase activity in budding yeast is downregulated in response to hydroxy-urea treatment that arrests cells in early S phase through inhibition of ribonucleo-tide reductase.18 Earlier work with human cells also concluded that the DDK activ-ity is inhibited upon etoposide treatment through the ATR-dependent inhibition of formation of the human DDK complex.21 However, more recent reports proposed that the human DDK is not inactivated under various genotoxic treatments.20,22 Recent reports showed that the human ASK/Dbf4 is a direct substrate of the upstream DNA damage response kinases ATM and/or ATR, and that such phos-phorylation of ASK/Dbf4 is required for activation of the so-called intra-S phase checkpoint that suppresses DNA repli-cation upon exposure of S-phase cells to ionizing radiation.23 This is consistent with the possibility that the human DDK function is downregulated upon genotoxic stress, which would lead to inhibition of the late origin firing. Interestingly, how-ever, the authors found that the phos-phorylation of ASK/Dbf4 did not affect the kinase activity of Cdc7, indicating that this regulatory phosphorylation may impact a currently unknown mechanism, such as regulation of some protein–pro-tein interactions that may facilitate sup-pression of late origin firing in human cells.23 It should be also noted that the human DDK activity is required for Chk1 activation, most probably through phos-phorylating Claspin, an adaptor protein essential for ATR-dependent phosphoryla-tion of Chk1,24,25 consistent with the idea that the DDK is active under replication stress.

Taken together, such divergent and partly contradictory reports highlight the important questions to be addressed regarding the human DDK: (1) Is the human DDK activity preserved under genotoxic/replication stress or not? (2) If it does remain active, is it only a certain subset of Cdc7 that is active, and what is the role of the DDK activity under such conditions?

In addition, although cell cycle-dependent regulation of transcription was reported for the components of the mam-malian DDK,4,26,27 it has been unclear whether and how the protein abundance of the DDK subunits is regulated upon replication block, and whether there are any differences in such regulatory mecha-nisms between unperturbed conditions vs. replication stress. Physiological and path-ological roles of the DDK activity under genotoxic stress should also be addressed, considering that DDK has been pro-posed as a promising target of anticancer treatment.28-35

Stabilization of DDK on Chromatin in Response

to Replication Stress

Recently, fresh insights have been pro-vided into these important issues. New results showed that under replication stress conditions, human DDK accumu-lates as an active complex on chromatin, and that such stabilization of the DDK protein components is mediated by the ATR–Chk1 kinase pathway-dependent inactivation of the anaphase-promoting complex/cyclosome-Cdh1(APC/CCdh1).36 The APC/CCdh1 ubiquitin ligase is one of the major cell cycle-regulatory machines, which becomes activated in later mitosis, remains active throughout the following G

1 phase, and then is switched off by the

enhanced CDK kinase activity (CDK1 and CDK2 in human cells) from the G

1/S

boundary until early M phase.37-40 Since the replication stress-responsive ATR–Chk1 signaling inhibits CDK activity (including CDK2 in S phase) via check-point pathways, such silencing of CDK could, in principle, lead to re-activation of the APC/CCdh1 at a “wrong” cell cycle phase, for example in S phase, thereby grossly deregulating the DNA replication factories and other S-phase factors. As the recent work clarified,36 this conundrum is solved through concomitant Chk1-medietad inactivation of the APC/CCdh1 complex, through promoting autodegra-dation of Cdh1 under replication stress conditions. Thus, the ATR–Chk1 axis silences the CDKs via checkpoints to delay replication, and at the same time ensures

that the APC/CCdh1- mediated proteolysis is not inappropriately activated in S phase.

Interestingly, and in contrast to replica-tion stress response in S phase, the APC/CCdh1 pathway becomes active in response to DNA double-strand breaks induced by X-ray irradiation or doxorubicin treat-ment, and this plays an important role in G

2 checkpoint activation through degra-

dation of PLK1, an essential kinase that regulates mitotic entry.41,42

It should be noted that DNA repair factors such as 53BP1 and Rap80 are among candidate substrates targeted for degradation by the APC/CCdh1 ubiquitin ligase,43,44 suggesting that the APC/CCdh1 pathway may be also involved in regula-tion of homologous recombination (HR), given a role of these proteins in restrict-ing DNA end resection, an essential step in HR.45,46

Furthermore, the DDK activity itself is required for the stabilization of the human Dbf4/ASK protein, suggesting that one of the important roles of the DDK activity under replication stress is to stabilize ASK/Dbf4, and thereby the DDK complex.36

Central Role of DDK in TLS-Mediated DNA Damage Repair:

Concept of the DDK-RAD18 Interaction as a Molecular Switch

in DNA Repair Pathway Choice

So, what could be the biological advan-tage for the active DDK to be stabilized on chromatin under replication stress? We believe, based on our own data36 and work done mainly on yeast models (see below), that the answer is in the choice of DNA repair pathway, in order to preserve genomic integrity while preventing collapse of the assembled replication fork machin-eries under conditions of replication stress. Previous studies in yeast strongly sug-gested that the DDK plays a crucial role in translesion synthesis (TLS),47,48 a mecha-nism that enables continued DNA replica-tion across the encountered DNA lesion. More recently, human DDK was shown to phosphorylate a cluster of serine residues on RAD18, and this positively regulates interaction between RAD18 and DNA polymerase η (Pol η).49,50 Furthermore, motif-C, a conserved C2H2-type zinc

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finger domain of the ASK/Dbf4 protein, interacts with the N-terminal region of RAD18, the ubiquitin ligase essential for TLS.36 This ASK/Dbf4–RAD18 interac-tion is required for chromatin binding of RAD18 and RAD18-mediated recruit-ment of Pol η, another key factor for TLS.36 Therefore, these results connect the ATR–Chk1 checkpoint pathway to the TLS pathway via the DDK. In addi-tion, the complex formation of RAD18-Pol η plays a key role in the recruitment of the complex to PCNA, through inter-action between the PIP box motif of Pol η and PCNA.51 Based on these studies, we propose here a conceptual model for how the checkpoint signaling regulates the TLS pathway in human cells. Thus, the checkpoint kinases help to stabilize the active DDK on chromatin to protect the replication fork from collapse and promote the TLS under replication stress caused by DNA lesions (Fig. 1).

Moreover, the observed interaction between the N-terminal region of RAD18, containing the RING domain, and the

ASK/Dbf436 raises an attractive hypothe-sis about the regulation of pathway choice under conditions of DNA damage/rep-lication stress (Fig. 2). Intriguingly, the RING domain of RAD18 also interacts with Rad51C, an essential factor for HR, and this interaction is required for the HR process to function.52 It should also be con-sidered that while the TLS pathway is one of the major pathways to continue DNA replication past the DNA lesion, the HR is an alternative pathway to restart DNA replication at the site of stalled fork, func-tioning predominantly during S phase and G

2 phases.53 Overall, the mechanistic

basis of a molecular switch between TLS and HR, for which we can now suggest a plausible scenario, has been poorly under-stood until now, certainly for human cells. The interaction between ASK/Dbf4 and RAD18 may suppress HR by preventing RAD18–Rad51C complex formation. Further enhancing the flexibility of this candidate regulatory “switch” role of the RING domain of RAD18, this domain also interacts with FANCD2, a protein

essential for repair of DNA inter-strand crosslinks by the Fanconi anemia (FA) pathway.54 We propose that the choice of the binding partner for RAD18’s RING domain may provide the long-thought switch mechanism, and determine which DNA repair pathway should be selected in face of a particular genotoxic insult or type of DNA lesions (Fig. 2). This hypothesis is also consistent with the observation that both chromatin binding and the foci formation of Rad51 and monoubiquitina-tion of FANCD2 are intact in ASK/Dbf4-depleted cells upon cisplatin treatment,36 suggesting that the interaction between ASK/Dbf4 and RAD18 specifically regu-lates the RAD18-dependent TLS, but not HR or FA pathways.

In order to sustain DNA replication across the DNA lesion, replisome (the replication fork complex) must be sta-bilized; otherwise the stalled fork would collapse, and, subsequently, a DNA double-strand break would be generated, which may undermine genomic integrity. In yeast, DDK plays a crucial role in fork

Figure  1. stabilization of chromatin-bound DDK upon replication stress and induction of tLs through DDK-mediated recruitment of rAD18–Pol η complex. (A) replication forks encounter a DNA lesion. (B) stalled forks activate the replication checkpoint, which stabilizes DDK on chromatin through inactivation of the APc/ccdh1 pathway. DDK phosphorylates rAD18 and facilitates interaction between rAD18 and Pol η. rAD18 monoubiquitinates PcNA, independently of DDK. (C) the DDK–rAD18-Pol η complex is loaded on chromatin to promote tLs.

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stabilization upon genotoxic insults.55,56 DDK-mutant yeast cells feature sponta-neous Rad52 foci, suggesting the ongo-ing rescue of collapsed forks by HR.56 An analogous role was also proposed for mammalian DDK,23,57 hence this func-tion of DDK in replisome stabilization to continue DNA replication across lesions appears to be conserved in all eukaryotes. Given that excessive HR can also compro-mise genome integrity, we speculate that by regulating pathway choice, DDK might also help to actively prevent untimely HR, a process that could be accomplished by modulating helicase activities of PARI, FBH1, or RTEL1, for example.58-60

Suppression of Late Origin Firing in Response to Replication Stress

At this moment, it is still unclear whether the entire pool of DDK stays active after exposure to replication stress. Although the bulk activity of DDK may be unaltered after the replication stress, it is possible that checkpoint kinase-mediated

phosphorylation may inactivate or pro-mote dissociation of at least a certain subset of Cdc7–ASK/Dbf4 complexes or those associated with the early-firing pre-RC, and thus render it unavailable for activation of late dormant origins.

If the human DDK remains active under replication stress conditions, how can the firing of late replication origins be suppressed without inhibiting the DDK function? Recently, a potential relevant role of a phosphatase was reported in Xenopus. In the Xenopus cell-free system, protein phosphatase 1 (PP1)-mediated dephosphorylation of MCM proteins, which is triggered by the checkpoint kinases, counteracts the DDK-dependent origin firing without modulating the DDK kinase activity.61 Thus, it might be an intriguing possibility that the check-point kinases activate PP1, which then counteracts the DDK-dependent phos-phorylation of the MCM complex to pre-vent late origin firing. However, there is currently no evidence either in Xenopus egg extracts or in any other systems that depletion or inactivation of phosphatases

override the checkpoint-mediated inhibi-tion of late origin firing. Nor is there any evidence that PP1 is indeed recruited to late origins upon replication stress. These issues need to be examined in the future to test this hypothesis.

Recently, Rif1, a telomere-binding fac-tor in yeasts, was found to be a major reg-ulator of replication timing in both yeasts and mammals.62-64 In the absence of Rif1, replication timing changes dramatically both in yeast and mammalian cells dur-ing normal cell cycle progression. In both species, timing and efficiency of pre-RC assembly is unaffected, but that of Cdc45 changes in the absence of Rif1.62,63 In fis-sion yeast, Rif1 binds close to the late/dor-mant origins and suppresses the firing of nearby origins62 (Kanoh et al. unpublished data). It is unknown whether mammalian Rif1 shows a similar binding preference. Nevertheless, the similarity is striking, in that the absence of Rif1 causes general loss of replication timing regulation through-out the genome.65 It is unlikely that Rif1 is involved in cellular responses to replica-tion stress, since rif1-null yeast cells and

Figure 2. A model for rAD18-dependent DNA repair pathway choice in response to genotoxic insults. rAD18 may function as a molecular switch for DDr pathway choice through alternating partner factors that bind to its riNG domain.

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Rif1-depleted human cells are resistant to HU.62,65 However, it is of interest that PP1 interacts with Rif1, and that this interac-tion may play a role in Rif1-mediated reg-ulation of replication timing in budding yeast.66

DDK and Cancer

Last but not least, we wish to discuss DDK in the context of tumorigenesis, and also as a candidate target for innovative cancer therapy. The major reason why the DDK-mediated response to replication stress is highly relevant for cancer is that activation of diverse oncogenes and loss of some tumor suppressors evoke replica-tion stress and consequent DNA damage that triggers the checkpoint responses of the ATR–Chk1 and ATM–Chk2 signal-ing cascades, as exemplified in cell culture experiments and documented by analy-ses of clinical specimens from a range of human malignancies.67-75 This anti-cancer barrier provided by the DNA damage checkpoints precedes the activation of the ARF tumor suppressor, the second anti-cancer barrier,76-80 and helps delay or prevent tumor progression by trigger-ing senescence or cell death among the nascent cancer cells.67,68,70,71 However, in those tumors that eventually do progress, the ATM-Chk2-p53 and other check-points are commonly bypassed or inac-tivated,67,72,73 while the ATR–Chk1 axis, which generally helps cells to cope with replication stress (as discussed above), remains operational, as cancer cells need to deal with the omnipresent challenge of enhanced replication stress.81 In such scenario, and given the above discussed roles of DDK under replication stress, the DDK activity (including the ASK/Dbf4-RAD18 role in TLS) may provide one of the stress-support functions on which can-cer cells depend more than their normal counterpart cells.

In addition, we suggest that the occur-rence of much greater endogenous replica-tion stress in cancer cells would provide opportunities for therapeutic intervention by DDK inhibitors. Indeed, several such scenarios could be proposed, as would be rationalized on the basis of the synthetic lethality principle, best documented by

the selective sensitivity of HR- (e.g., BRCA1/2-) defective tumors to PARP inhibitors.82-85 Since the HR pathway is impaired in BRCA-deficient tumors, small-molecule inhibitors of Cdc7 kinase activity (and/or inhibitors of RAD18 ubiquitin ligase, yet to be developed) could be useful as an alternative of PARP inhibi-tors. Indeed, it has been shown that the HR pathway is required for the viability of rad18Δ yeast cells upon chronic low-dose UV light exposure.86,87 It was also reported that double mutants for RAD18 and RAD54, a gene required for HR, exhibit synthetic lethality in chicken DT40 cells, in contrast to only modest impact of either mutation alone.88 Moreover, human cells deficient in the TLS pathway, including RAD18 deficiency, are hypersensitive to cisplatin treatment,89 whose tolerance is also dependent on the HR pathway. Since the FA pathway is proposed to be involved in HR,90-95 the Cdc7 kinase inhibitors could be also effective for tumors in which the FA pathway is impaired.

In conclusion, targeting the DDK activity under conditions of enhanced replication stress and the nodal point of RAD18 interactions in DNA repair pathway choice may inspire novel treat-ment strategies in oncology. Such DDK/RAD18-antagonizing drugs could be used as single treatment in subsets of patients selected based on suitable biomarker infor-mation on the DNA repair pathway status and extent of replication stress.67,70,81,96,97 Alternatively, they could be combined with standard-of-care genotoxic che-motherapeutics or ionizing radiation to obtain higher sensitization of cancer cells.

Despite the undisputable progress in recent years, a great deal remains to be done to mechanistically understand the cellular responses to replication stress in general, and the role(s) of the DDK in checkpoint responses and DNA repair in particular. Given the numerous emerg-ing fertile avenues of this research, it is clear that this fascinating field will move even more rapidly, and into the forefront of basic and likely also translational bio-medical research.

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.

Acknowledgments

The work in the authors’ labora-tories is supported by grants from the Danish Cancer Society, European Commission (projects DDResponse and Biomedreg: CZ.1.05/2.1.00/01.0030), the Grant Agency of the Czech Republic (GA13-17555S), the Internal Grant Agency of the Czech Ministry of Health (grant NT11065-5), the Danish National Research Foundation, the Lundbeck Foundation, the Novo Nordisk Foundation, the Kellner Family Foundation, and the Danish Research Council.

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