Dbf4 Is Direct Downstream Target of Ataxia Telangiectasia Mutated (ATM) and Ataxia Telangiectasia and Rad3-related (ATR) Protein to Regulate Intra-S-phase Checkpoint

Lee, Alan Yueh‐Luen; Chiba, Takuya; Truong, Lan N.; Cheng, An; Do, Johnny; Cho, Michael Jeffrey; Chen, Longchuan; Wu, Xiaohua

doi:10.1074/jbc.m111.291104

Cited by 45 publications

(60 citation statements)

References 71 publications

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“…Here we show that, somewhat unexpectedly, in human somatic cells, an active Cdc7-ASK kinase complex resides on chromatin upon DNA replication block. Our data are consistent with some previous observations (Tenca et al 2007;Lee et al 2012). For example, Lee et al (2012) reported that human ASK is phosphorylated by ATM/ATR upon various genotoxic insults, and such phosphorylation is involved in the checkpoint response; however, the investigators failed to detect suppression of Cdc7 kinase activity.…”

Section: Cdc7 Kinase Activity In Human Cells Under Replication Stresssupporting

confidence: 94%

“…Our data are consistent with some previous observations (Tenca et al 2007;Lee et al 2012). For example, Lee et al (2012) reported that human ASK is phosphorylated by ATM/ATR upon various genotoxic insults, and such phosphorylation is involved in the checkpoint response; however, the investigators failed to detect suppression of Cdc7 kinase activity. Collectively, these studies raise the intriguing question of how such seemingly conflicting results can be reconciled.…”

Section: Cdc7 Kinase Activity In Human Cells Under Replication Stresssupporting

confidence: 94%

“…Stabilization and chromatin binding of active Cdc7-ASK upon DNA replication block Previous reports reached mutually contradictory conclusions about changes of chromatin binding, active complex formation, and activity of Cdc7 kinase upon genotoxic stress (Costanzo et al 2000;Dierov et al 2004;Tenca et al 2007;Lee et al 2012). To address this important issue, we first assessed the kinetics of chromatin binding of Cdc7-ASK in U2OS cells exposed to various genotoxic stresses.…”

Section: Resultsmentioning

confidence: 98%

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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

et al. 2013

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Cdc7 kinase regulates DNA replication. However, its role in DNA repair and recombination is poorly understood. Here we describe a pathway that stabilizes the human Cdc7-ASK (activator of S-phase kinase; also called Dbf4), its regulation, and its function in cellular responses to compromised DNA replication. Stalled DNA replication evoked stabilization of the Cdc7-ASK (Dbf4) complex in a manner dependent on ATR-Chk1-mediated checkpoint signaling and its interplay with the anaphase-promoting complex/cyclosome Cdh1 (APC/C Cdh1 ) ubiquitin ligase. Mechanistically, Chk1 kinase inactivates APC/C Cdh1 through degradation of Cdh1 upon replication block, thereby stabilizing APC/C Cdh1 substrates, including Cdc7-ASK (Dbf4). Furthermore, motif C of ASK (Dbf4) interacts with the N-terminal region of RAD18 ubiquitin ligase, and this interaction is required for chromatin binding of RAD18. Impaired interaction of ASK (Dbf4) with RAD18 disables foci formation by RAD18 and hinders chromatin loading of translesion DNA polymerase h. These findings define a novel mechanism that orchestrates replication checkpoint signaling and ubiquitin-proteasome machinery with the DNA damage bypass pathway to guard against replication collapse under conditions of replication stress.

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Section: Cdc7 Kinase Activity In Human Cells Under Replication Stresssupporting

confidence: 94%

Section: Cdc7 Kinase Activity In Human Cells Under Replication Stresssupporting

confidence: 94%

Section: Resultsmentioning

confidence: 98%

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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

et al. 2013

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“…S5C) (30). We expressed DD-HA-I-SceI-GR in T98G (MMEJ) single integration cell lines and assayed for MMEJ.…”

Section: Mre11mentioning

confidence: 99%

Microhomology-mediated End Joining and Homologous Recombination share the initial end resection step to repair DNA double-strand breaks in mammalian cells

Truong

Shi

et al. 2013

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

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425

453

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Microhomology-mediated end joining (MMEJ) is a major pathway for Ku-independent alternative nonhomologous end joining, which contributes to chromosomal translocations and telomere fusions, but the underlying mechanism of MMEJ in mammalian cells is not well understood. In this study, we demonstrated that, distinct from Ku-dependent classical nonhomologous end joining, MMEJ-even with very limited end resection-requires cyclin-dependent kinase activities and increases significantly when cells enter S phase. We also showed that MMEJ shares the initial end resection step with homologous recombination (HR) by requiring meiotic recombination 11 homolog A (Mre11) nuclease activity, which is needed for subsequent recruitment of Bloom syndrome protein (BLM) and exonuclease 1 (Exo1) to DNA double-strand breaks (DSBs) to promote extended end resection and HR. MMEJ does not require S139-phosphorylated histone H2AX (γ-H2AX), suggesting that initial end resection likely occurs at DSB ends. Using a MMEJ and HR competition repair substrate, we demonstrated that MMEJ with short end resection is used in mammalian cells at the level of 10-20% of HR when both HR and nonhomologous end joining are available. Furthermore, MMEJ is used to repair DSBs generated at collapsed replication forks. These studies suggest that MMEJ not only is a backup repair pathway in mammalian cells, but also has important physiological roles in repairing DSBs to maintain cell viability, especially under genomic stress.BLM/Exo1 | CtIP | DNA repair pathway | DNA damage | genome stability D NA double-strand breaks (DSBs) can be repaired by multiple pathways. The classical nonhomologous end joining (C-NHEJ) pathway relies on Ku70/Ku80 and ligates DSB ends without a template (1). Homologous recombination (HR), an error-free pathway, uses a homologous template to repair DSBs (2) and is initiated by end resection from DSB ends to generate a long stretch of singlestrand DNA (ssDNA) for strand invasion. Although C-NHEJ is active throughout the cell cycle, HR is used when cells enter S and G2 because cyclin-dependent kinases (CDKs) are needed for promoting end resection to activate HR (3-5).In the absence of C-NHEJ factors such as Ku70, Ku80, or DNA ligase IV, robust alternative nonhomologous end joining (alt-NHEJ) activity is observed in various organisms including yeast and mammals (6, 7). Many alt-NHEJ events, classified as microhomology-mediated end joining (MMEJ), require end resection and join the ends by base pairing at microhomology sequences (5-25 nucleotides), resulting in deletions at the junctions (6). However, other alt-NHEJ pathways without using microhomology regions also exist.Genetic analyses in yeast reveal that MMEJ is Rad52-independent, distinguishing it from HR and single-strand annealing (SSA) repair pathways, whereas the Mre11-Rad50-Xrs2 (MRX) complex and DNA ligase IV are needed for MMEJ (8-10). Further studies suggest that in yeast, Srs2 helicase, Sae2 nuclease [CtBP-interacting protein (CtIP) homologue], Tel1 [ataxia telangiectasia mutated (A...

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“…Moreover, we have reported that ATM regulates Dbf4-dependent protein kinase (DDK), and the Mre11/ Rad50/Nbs1 (MRN) complex, both of which are important for the maintenance of genome integrity, for protection against tumor development [41][42][43] . Furthermore, ATM may directly interact with and phosphorylate FoxO1 in the case of DNA damage 44) .…”

Section: Potential Role Of Hnf-4α In the Suppression Of Tumor Developmentioning

confidence: 99%

Mechanisms of lifespan extension and preventive effects of calorie restriction on tumor development: Possible link between central neuroendocrine system and peripheral metabolic adaptation

Chiba

Dong

Nishizono

et al. 2013

JPFSM

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Restriction of food intake (calorie restriction [CR]) in laboratory animals extends their lifespan and delays the onset of various age-associated diseases, including cancer development. Recent studies revealed that the molecular mechanisms underlying CR-mediated antiaging effects may be regulated by a confined number of signal transduction pathways that are triggered by neuropeptide Y (NPY) neurons in the neuroendocrine system. On the other hand, possible peripheral regulators of the beneficial effects of CR involve a transcriptional regulator complex, the hepatocyte nuclear factor 4α/peroxisome proliferator-activated receptor gamma coactivator 1-α (HNF-4α/PGC-1α) complex. This complex could regulate not only glucose and lipid metabolism, but also DNA damage responses in the liver. Therefore, maintenance of optimal glucose and lipid levels to prevent metabolic syndrome, and activation of the DNA damage response for suppression of tumor development, may depend on the HNF-4α/PGC-1α complex. Hence, small molecules modulating the activity of this complex could be an important target for development of CR mimetics (CRM), which mimic the beneficial effects of CR without actual food restriction.

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Dbf4 Is Direct Downstream Target of Ataxia Telangiectasia Mutated (ATM) and Ataxia Telangiectasia and Rad3-related (ATR) Protein to Regulate Intra-S-phase Checkpoint

Cited by 45 publications

References 71 publications

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

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

Microhomology-mediated End Joining and Homologous Recombination share the initial end resection step to repair DNA double-strand breaks in mammalian cells

Mechanisms of lifespan extension and preventive effects of calorie restriction on tumor development: Possible link between central neuroendocrine system and peripheral metabolic adaptation

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Dbf4 Is Direct Downstream Target of Ataxia Telangiectasia Mutated (ATM) and Ataxia Telangiectasia and Rad3-related (ATR) Protein to Regulate Intra-S-phase Checkpoint

Cited by 45 publications

References 71 publications

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

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

Microhomology-mediated End Joining and Homologous Recombination share the initial end resection step to repair DNA double-strand breaks in mammalian cells

Mechanisms of lifespan extension and preventive effects of calorie restriction on tumor development: Possible link between central neuroendocrine system and peripheral metabolic adaptation

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Product

Resources

About

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

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