p300/CREB-binding Protein Interacts with ATR and Is Required for the DNA Replication Checkpoint

Stauffer, Daniel; Chang, Bill H.; Huang, Jing; Dunn, Andrew; Thayer, Mathew J.

doi:10.1074/jbc.m609261200

Cited by 41 publications

(39 citation statements)

References 59 publications

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“…Importantly, both ATM and Chk2 were found to be phosphorylated at significant levels. An earlier study showed that p300 depletion in HeLa cells does not result in Chk1 phosphorylation, suggesting that ATR/Chk1 pathway is not active during p300 down-regulation (22). We have confirmed these results (data not shown).…”

Section: Down-regulation Of P300 In Human Cellssupporting

confidence: 88%

“…The role of p300/CBP in the cellular response to DNA damage is likely to be more complex than that described above, as a recent large scale proteomic study showed that more than 700 proteins are phosphorylated after ionizing radiation (40). A recent study carried out in HeLa cells showed that Chk1 phosphorylation was dependent on ablation of both p300 and CBP (22). In contrast, in MCF10A, which are immortalized human breast epithelial cells, depletion of p300 alone was sufficient to activate the DNA damage response.…”

Section: Discussionmentioning

confidence: 98%

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c-Myc-induced Aberrant DNA Synthesis and Activation of DNA Damage Response in p300 Knockdown Cells

Natesan

Kadeppagari²,

Thimmapaya

2009

Journal of Biological Chemistry

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We previously showed that in quiescent cells, p300/CBP (CREB-binding protein)family coactivators repress c-myc and prevent premature induction of DNA synthesis. p300/CBP-depleted cells exit G 1 early and continue to accumulate in S phase but do not progress into G 2 /M, and eventually they die of apoptosis. Here, we show that the S-phase arrest in these cells is because of an intra-S-phase block. The inappropriate DNA synthesis that occurs as a result of forced expression of c-myc leads to the activation of the DNA damage response as evidenced by the phosphorylation of several checkpoint related proteins and the formation of foci containing ␥-H2AX. The activation of checkpoint response is related to the induction of c-myc, as the phosphorylation of checkpoint proteins can be reversed when cells are treated with a c-Myc inhibitor or when Myc synthesis is blocked by short hairpin RNA. Using the DNA fiber assay, we show that in p300-depleted cells initiation of replication occurs from multiple replication origins. Chromatin loading of the Cdc45 protein also indicates increased origin activity in p300 knockdown cells. Immunofluorescence experiments indicate that c-Myc colocalizes with replication foci, consistent with the recently reported direct role of c-Myc in the initiation of DNA synthesis. Thus, the inappropriate S-phase entry of p300 downregulated cells is likely to be because of c-Myc-induced deregulated replication origin activity, which results in replicative stress, activation of a DNA damage response, and S-phase arrest. Our results point to an important role for p300 in maintaining genomic integrity by negatively regulating c-myc.In eukaryotic cells, initiation of DNA replication takes place from multiple replication origins on each chromosome, providing flexibility for the large eukaryotic DNA to replicate efficiently. However, control mechanisms exist to ensure that DNA replication occurs only once per cell, and when such mechanisms fail, checkpoint responses are activated to monitor the genome integrity and inhibit replication until DNA damage has been repaired (for review, see Ref. 1). In response to DNA damage, eukaryotic cells activate ATM 3 /Chk2 and ATR/Chk1 kinase pathways to arrest the cell cycle and allow time to repair DNA. Both ATM and ATR control cell cycle checkpoint signals by phosphorylating a number of checkpoint-related proteins including Chk1 and Chk2 and p53 (for review, see Refs. 2 and 3). p300 and CBP are two highly related and conserved nuclear phosphoproteins that function as transcriptional coactivators, and by interacting with a large number of sequence-specific transcription factors they integrate diverse signal transduction pathways in the nucleus. Because of their intrinsic histone acetyltransferase activity, they also acetylate nucleosomal histones and, thus, link chromatin remodeling with transcription (for review, see Ref. 4). Recent studies suggest that p300/CBP plays an important role in DNA replication and the activation of DNA damage response by interacting with seve...

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Section: Down-regulation Of P300 In Human Cellssupporting

confidence: 88%

Section: Discussionmentioning

confidence: 98%

c-Myc-induced Aberrant DNA Synthesis and Activation of DNA Damage Response in p300 Knockdown Cells

Natesan

Kadeppagari²,

Thimmapaya

2009

Journal of Biological Chemistry

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“…The prevailing assumption is that some CBP or p300 protein is required for cell viability or proliferation, as shown for mouse lymphocytes in vivo 31, 32. Consistent with this view, RNA interference (RNAi) mediated knockdown of CBP and p300 in immortal HeLa cells results in cell death due to “mitotic catastrophe” and “chromosome shredding.”33 Similarly, RNAi knockdown of dCBP in Drosophila kc cells also leads to cell death 34. These RNAi studies indicate that this approach is not generally applicable for knocking down CBP/p300 in cell lines for transcription experiments.…”

Section: Cells That Lack Cbp and P300mentioning

confidence: 99%

Target gene context influences the transcriptional requirement for the KAT3 family of CBP and p300 histone acetyltransferases

Bedford¹,

Kasper²,

Brindle³

2010

Epigenetics

257

243

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“…Numerous investigations have shown the among proteins known to the transcriptional co-activator p300/CBP deserves DNA damage that control G2/M regulation and delayed entry into mitosis correlation with cdc2/cyclin B1 association [29]. To demonstrate the effect of CIL-102 on the cell-cycle-related proteins and the kinase-signaling pathway, we assessed whole-cell lysates from erinacine A–treated DLD-1 cells by Western blot analysis using antibodies against the expressed forms of p21 and GADD45 as well as NFκB p50/p300/CBP.…”

Section: Resultsmentioning

confidence: 99%

CIL-102-Induced Cell Cycle Arrest and Apoptosis in Colorectal Cancer Cells via Upregulation of p21 and GADD45

Huang

Kuo

et al. 2017

PLoS ONE

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CIL-102 (1-[4-(furo[2,3-b]quinolin-4-ylamino)phenyl]ethanone) is a well-known, major active agent of the alkaloid derivative of Camptotheca acuminata with valuable biological properties, including anti-tumorigenic activity. In this study, we investigated the molecular mechanisms by which CIL-102 mediated the induction of cell death, and we performed cell cycle G2/M arrest to clarify molecular changes in colorectal cancer cells (CRC). Treatment of DLD-1 cells with CIL-102 resulted in triggering the extrinsic apoptosis pathway through the activation of Fas-L, caspase-8 and the induction of Bid cleavage and cytochrome c release in a time-dependent manner. In addition, CIL-102 mediated apoptosis and G2/M arrest by phosphorylation of the Jun N-terminus kinase (JNK1/2) signaling pathway. This resulted in the expression of NFκB p50, p300 and CREB-binding protein (CBP) levels, and in the induction of p21 and GADD45 as well as the decreased association of cdc2/cyclin B. Furthermore, treatment with the JNK1/2 (SP600125), NFκB (PDTI) or the p300/CBP (C646) inhibitors abolished CIL-102-induced cell cycle G2/M arrest and reversed the association of cdc2 with cyclin B. Therefore, we demonstrated that there was an increase in the cellular levels of p21 and GADD45 by CIL-102 reduction in cell viability and cell cycle arrest via the activation of the JNK1/2, NFκB p50, p300 and CBP signaling modules. Collectively, our results demonstrated that CIL-102 induced cell cycle arrest and apoptosis of colon cancer cells by upregulating p21 and GADD45 expression and by activating JNK1/2, NFκB p50 and p300 to provide a new mechanism for CIL-102 treatment.

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p300/CREB-binding Protein Interacts with ATR and Is Required for the DNA Replication Checkpoint

Cited by 41 publications

References 59 publications

c-Myc-induced Aberrant DNA Synthesis and Activation of DNA Damage Response in p300 Knockdown Cells

c-Myc-induced Aberrant DNA Synthesis and Activation of DNA Damage Response in p300 Knockdown Cells

Target gene context influences the transcriptional requirement for the KAT3 family of CBP and p300 histone acetyltransferases

CIL-102-Induced Cell Cycle Arrest and Apoptosis in Colorectal Cancer Cells via Upregulation of p21 and GADD45

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