ATR–Chk1–APC/C<sup>Cdh1</sup>-dependent stabilization of Cdc7–ASK (Dbf4) kinase is required for DNA lesion bypass under replication stress

Yamada, Masayuki; Watanabe, Kenji; Mistrík, Martin; Vesela, Eva; Protivankova, Iva; Mailand, Niels; Lee, Myung‐Hee; Masai, Hisao; Lukáš, Jiří; Bártek, Jiří

doi:10.1101/gad.224568.113

Cited by 74 publications

(107 citation statements)

References 71 publications

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“…The bestcharacterized ATR effector, to date, is Chk1 (Zhao and PiwnicaWorms, 2001), which is activated through ATR-mediated phosphorylation at residues S317 and S345 (Liu et al, 2000) in a reaction that is stimulated by claspin binding to Chk1 (Lindsey- Boltz et al, 2009), by the 9-1-1 complex (Liu et al, 2012;Wang et al, 2006) and RHINO (Lindsey-Boltz et al, 2015), as well as by other factors (Nam and Cortez, 2011) (see poster). Chk1 activation stabilizes the chromatin-bound CDC7-DBF4 apoptosis signalregulating kinase (ASK) complex, which assists in replication and origin firing (Yamada et al, 2013). Chk1 affects progression through S phase at the level of origin firing, replication elongation and fork integrity (Brown and Baltimore, 2003;Heffernan et al, 2007;Petermann et al, 2006Petermann et al, , 2010Segurado and Diffley, 2008;Zhao et al, 2002).…”

Section: Atr In Cell Cycle Regulationmentioning

confidence: 99%

ATM and ATR signaling at a glance

Awasthi

Foiani

Kumar

2015

Journal of Cell Science

232

228

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There was an error published in J. Cell Sci. 128, 4255-4262.An incorrect citation and reference was given for the last sentence in Box 2. The correct citation and reference are: A recent review provides a detailed update on ATM and ATR inhibitors, and their potential as drug targets (Weber and Ryan, 2015).Weber, A.M. and Ryan, A.J. (2015). ATM and ATR as therapeutic targets in cancer. Pharmacol Ther. 149, 124-138.The authors apologise to the readers for any confusion that this error might have caused. Although the role of both ATM and ATR in DNA repair, cell cycle regulation and apoptosis have been well studied, both still remain in the focus of current research activities owing to their role in cancer. Recent advances in the field suggest that these proteins have an additional function in maintaining cellular homeostasis under both stressed and non-stressed conditions. In this Cell Science at a Glance article and the accompanying poster, we present an overview of recent advances in ATR and ATM research with emphasis on that into the modes of ATM and ATR activation, the different signaling pathways they participate in -including those that do not involve DNA damage -and highlight their relevance in cancer. 1285

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Section: Atr In Cell Cycle Regulationmentioning

confidence: 99%

ATM and ATR signaling at a glance

Awasthi

Foiani

Kumar

2015

Journal of Cell Science

232

228

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“…Since blocking DDK activity largely prevents CHK1 phosphorylation upon exposure to replication stress [14,16, 17], we analyzed how DDK influences the overall checkpoint response induced by HU. We found that 5 µM of DDKi and a pre-treatment time of 4 hours were required to substantially block CHK1 activation by HU in HCC1954 cells (Supplementary Figure 1A).…”

Section: Ddk Has a Primary Role In Initiating Replication Checkpoint mentioning

confidence: 99%

“…However, subsequent studies reported that human DDK is active during replication stress and has an upstream role to fully activate the checkpoint kinase CHK1 [13,14]. In response to exogenous replication inhibitors, DDK recruitment to chromatin is increased [13,14], CDC7-DBF4 complex is stabilized [13], and MCM shows increased phosphorylation at several DDK-specific sites [13,15]. DDK promotes CHK1 phosphorylation partly through binding to and phosphorylating Claspin, an adaptor protein required for CHK1 activation [16, 17].…”

Section: Introductionmentioning

confidence: 99%

DDK has a primary role in processing stalled replication forks to initiate downstream checkpoint signaling

Sasi

Coquel

Lin

et al. 2017

Preprint

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Abstract:CDC7-DBF4 kinase (DDK) is required to initiate DNA replication in eukaryotes by activating the replicative MCM helicase. DDK has also been reported to have diverse and sometimes conflicting roles in the replication checkpoint response in various organisms but the underlying mechanisms are far from settled. Here we show that human DDK promotes limited resection of newly synthesized DNA at stalled replication forks or sites of DNA damage to initiate replication checkpoint signaling. DDK is also required for efficient fork restart and G2/M cell cycle arrest. DDK exhibits genetic interactions with the ssDNA exonuclease EXO1, and we show that EXO1 is also required for nascent strand degradation following exposure to HU, raising the possibility that DDK regulates EXO1 directly. Thus, DDK has a primary and previously undescribed role in the replication checkpoint to promote ssDNA accumulation at stalled forks, which is required to initiate a robust checkpoint response and cell cycle arrest to maintain genome integrity.Keywords: DNA replication checkpoint/ replication fork/ fork resection/ fork restart/ DDK peer-reviewed) is the author/funder. All rights reserved. No reuse allowed without permission.The copyright holder for this preprint (which was not . http://dx.doi.org/10.1101/207266 doi: bioRxiv preprint first posted online 3 DDK is a two-subunit kinase that is essential to initiate DNA replication at individual replication origins by phosphorylating and activating the MCM2-7 replicative helicase. The regulatory subunit DBF4 binds to CDC7 and is required for its kinase activity [1]. DDK also has roles in replication checkpoint signaling that are less well understood [1]. In budding yeast, DDK is a target of the checkpoint effector kinase Rad53 that is activated following replication stress [2]. Rad53-mediated phosphorylation of Dbf4 modestly reduces DDK activity [2] and also inhibits late origin firing [3,4], but there is also evidence that DDK is required for the complete activation of Rad53 kinase [5]. In fission yeast, DDK subunits Hsk1 and Dfp1 are phosphorylated upon HU treatment by the checkpoint kinase Cds1, orthologous to budding yeast Rad53 and mammalian CHK2 [6][7][8]. Deletion of either Cds1 or its activating protein Mrc1 partially rescues the temperature sensitivity of hsk1-1312 mutants suggesting that Cds1 (like Rad53) inhibits DDK activity [8,9]. Cds1 activation in response to HU, however, was reduced significantly in hsk1(ts) strains at restrictive temperature and the cell cycle arrest was also aberrant as seen by an increased population of 'cut' cells (indicative of mitosis without complete DNA replication) [8,10]. These paradoxical results in yeast could be explained by a negative feedback loop where DDK first helps to initiate replication checkpoint activation and then the checkpoint pathway subsequently alters DDK activity to inhibit late origin firing.Initial studies in human cells showed that the replication checkpoint inhibits DDK activity, presumably to inhibit origin firing [11,...

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“…Based on the current report, we infer that DDK must be active during DNA damage checkpoint activation to allow for TLS. Similarly, human DDK on chromatin remains active during checkpoint activation to facilitate TLS by Polh (Yamada et al 2013). It was proposed there are two distinct pools of DDK with the soluble pool inhibited to block late origin firing, while the chromatinbound pool remains active to facilitate TLS (Yamada et al 2013).…”

Section: Discussionmentioning

confidence: 99%

“…Based on biochemical analyses, we suggest DDK regulates mutagenesis by direct interaction with and phosphorylation of the Rev7 subunit of Polz. Our results are important, given the conservation of DDK's role in TLS in human cells (Day et al 2010;Yamada et al 2013), and are significant with regard to human disease because overexpression of yeast DDK increases mutagenesis (Sclafani et al 1988;Sclafani and Jackson 1994), human DDK overexpression is observed in many types of cancer cells (Hess et al 1998;Nambiar et al 2007;Bonte et al 2008;Clarke et al 2009;Kulkarni et al 2009), and DDK is a therapeutic target in cancer patients (Rodriguez-Acebes et al 2010).…”

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confidence: 99%

The Role of Dbf4-Dependent Protein Kinase in DNA Polymerase ζ-Dependent Mutagenesis in Saccharomyces cerevisiae

et al. 2014

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The yeast Dbf4-dependent kinase (DDK) (composed of Dbf4 and Cdc7 subunits) is an essential, conserved Ser/Thr protein kinase that regulates multiple processes in the cell, including DNA replication, recombination and induced mutagenesis. Only DDK substrates important for replication and recombination have been identified. Consequently, the mechanism by which DDK regulates mutagenesis is unknown. The yeast mcm5-bob1 mutation that bypasses DDK's essential role in DNA replication was used here to examine whether loss of DDK affects spontaneous as well as induced mutagenesis. Using the sensitive lys2DA746 frameshift reversion assay, we show DDK is required to generate "complex" spontaneous mutations, which are a hallmark of the Polz translesion synthesis DNA polymerase. DDK co-immunoprecipitated with the Rev7 regulatory, but not with the Rev3 polymerase subunit of Polz. Conversely, Rev7 bound mainly to the Cdc7 kinase subunit and not to Dbf4. The Rev7 subunit of Polz may be regulated by DDK phosphorylation as immunoprecipitates of yeast Cdc7 and also recombinant Xenopus DDK phosphorylated GST-Rev7 in vitro. In addition to promoting Polzdependent mutagenesis, DDK was also important for generating Polz-independent large deletions that revert the lys2DA746 allele. The decrease in large deletions observed in the absence of DDK likely results from an increase in the rate of replication fork restart after an encounter with spontaneous DNA damage. Finally, nonepistatic, additive/synergistic UV sensitivity was observed in cdc7D pol32D and cdc7D pol30-K127R,K164R double mutants, suggesting that DDK may regulate Rev7 protein during postreplication "gap filling" rather than during "polymerase switching" by ubiquitinated and sumoylated modified Pol30 (PCNA) and Pol32. K NOWLEDGE of how mutations are produced is important for understanding genetic variability in populations and the process of evolution. Cells have evolved sophisticated molecular mechanisms for maintaining the integrity of the genome. Most DNA repair mechanisms have high fidelity and prevent mutations by removing damaged DNA and replacing the resulting gap using the undamaged, complementary strand as a template (Waters et al. 2009;Boiteux and Jinks-Robertson 2013). If not repaired, some lesions block the replicative DNA polymerases (Pols a, d, and e) during S phase and require bypass by an alternative errorfree or error-prone mechanism. Error-free bypass usually involves a template switch to the undamaged sister chromatid, while error-prone bypass uses translesion synthesis (TLS) DNA polymerases to synthesize new DNA directly across the lesion. There are at least 15 identified TLS polymerases in human cells but only three in the yeast Saccharomyces cerevisiae: Polz, Polh, and Rev1, which are encoded by the REV3-REV7, RAD30, and REV1 genes, respectively (Boiteux and Jinks-Robertson 2013). TLS polymerases have low fidelity and processivity on undamaged DNA templates and lack an associated exonuclease proofreading activity.The misregulation or loss of TLS p...

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ATR–Chk1–APC/C^Cdh1-dependent stabilization of Cdc7–ASK (Dbf4) kinase is required for DNA lesion bypass under replication stress

Cited by 74 publications

References 71 publications

ATM and ATR signaling at a glance

ATM and ATR signaling at a glance

DDK has a primary role in processing stalled replication forks to initiate downstream checkpoint signaling

The Role of Dbf4-Dependent Protein Kinase in DNA Polymerase ζ-Dependent Mutagenesis in Saccharomyces cerevisiae

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ATR–Chk1–APC/CCdh1-dependent stabilization of Cdc7–ASK (Dbf4) kinase is required for DNA lesion bypass under replication stress

Cited by 74 publications

References 71 publications

ATM and ATR signaling at a glance

ATM and ATR signaling at a glance

DDK has a primary role in processing stalled replication forks to initiate downstream checkpoint signaling

The Role of Dbf4-Dependent Protein Kinase in DNA Polymerase ζ-Dependent Mutagenesis in Saccharomyces cerevisiae

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ATR–Chk1–APC/C^Cdh1-dependent stabilization of Cdc7–ASK (Dbf4) kinase is required for DNA lesion bypass under replication stress