c-Abl tyrosine kinase in the DNA damage response: cell death and more

Meltser, V; Ben-Yehoyada, Merav; Shaul, Yosef

doi:10.1038/cdd.2010.132

Cited by 38 publications

(42 citation statements)

References 22 publications

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“…Accordingly, we have established that perturbed chromatin organization promotes KAT5 chromatin binding and the concurrent accumulation of KAT5 Tyr phosphorylation, which in turn induces ATM-mediated signaling and cell cycle checkpoint activation. These results help explain earlier observations regarding ATM activation upon chromatin alterations 11,18 and extend on previous studies linking c-Abl to DNA-damage responses [21][22][23][24] . While previous reports have indicated that c-Abl activity is enhanced upon genotoxic stress 20,24 , our data indicate that basal c-Abl kinase activity 29 is sufficient for the accumulation of Tyr-phosphorylated KAT5 at sites of DNA damage and chromatin perturbation.…”

Section: Discussionsupporting

confidence: 80%

“…While previous reports have indicated that c-Abl activity is enhanced upon genotoxic stress 20,24 , our data indicate that basal c-Abl kinase activity 29 is sufficient for the accumulation of Tyr-phosphorylated KAT5 at sites of DNA damage and chromatin perturbation. Nevertheless, it seems quite possible that previously-reported DNA damagemediated activation mechanisms for c-Abl 21,23,24 serve to strengthen signaling from DSB sites and perhaps other genomic lesions. It is tempting to speculate that the events that we have defined may contribute to the signatures of DDR signaling that are observed in progeria cells, where heterochromatin organization is perturbed 30 due to, for example, loss of HP1 proteins 31 or the NuRD (nucleosome remodeling and deacetylase) complex 32 .…”

Section: Discussionmentioning

confidence: 99%

“…Our initial analyses ruled out a dependency of KAT5 tyrosine phosphorylation on the DSB responsive kinases ATM and DNA-PK, as their inhibition had no discernible effect on KAT5 phosphorylation ( Supplementary Fig 10). Subsequently, through assessing various potential KAT5 kinases, we focused on the tyrosine kinase c-Abl, which has previously been implicated in DDR events [20][21][22][23][24] . As expected, pre-treating human RPE1 cells with the small-molecule c-Abl inhibitor, imatinib 25 , abolished c-Abl auto-phosphorylation on Tyr-245 ( Fig.…”

Section: C-abl Targets Kat5 Tyr-44 To Promote Atm-mediated Signalingmentioning

confidence: 99%

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KAT5 tyrosine phosphorylation couples chromatin sensing to ATM signalling

Kaidi

Jackson

2013

Nature

150

175

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Detecting genomic changes represents a critical step in cellular responses to DNA damage. Here, we show that tyrosine phosphorylation of the protein acetyltransferase KAT5 (Tip60) increases in response to DNA damage in a manner that promotes KAT5 binding to the histone mark H3K9me3. This in turn triggers KAT5-mediated acetylation of the ATM kinase, promoting DNAdamage checkpoint activation and cell survival. We also establish that chromatin alterations per se can enhance KAT5 tyrosine phosphorylation and ATM-dependent signaling, and identify the proto-oncogene c-Abl as mediating this modification. These findings define KAT5 as a key sensor for genomic and chromatin perturbations, and highlight a prime role for c-Abl in such events.Maintenance of genome integrity is pivotal for cellular fitness 1 , wherein sensing genomic changes represents a critical step 2 . In response to DNA double-strand breaks (DSBs) within genomic DNA, chromatin organization is altered in an orchestrated manner to facilitate the cellular DNA damage response (DDR) 3,4 . One aspect of the DDR is checkpoint activation, which primarily slows or halts cell cycle progression 5 . Central to checkpoint signaling following DSB induction is the protein kinase ATM 6 . While ATM activation is clearly instigated by its association with the MRE11-RAD50-NBS1 (MRN) complex at DSB sites [7][8][9][10] , accumulating evidence suggests that ATM activity is potentiated by mechanisms that sense and respond to chromatin alterations in the context of DNA damage 11,12 . Accordingly, it was found that binding of the protein lysine acetyltransferase KAT5 (Tip60) to histone H3 trimethylated at lysine 9 (H3K9me3) promotes KAT5-dependent acetylation of ATM, thereby enhancing ATM activity 12 . How and whether KAT5 binding to H3K9me3 is regulated, however, has not yet been established. Here, we identify the accumulation of KAT5 tyrosine phosphorylation as a part of a mechanism for sensing chromatin alterations, including those generated after DNA damage, thereby promoting checkpoint signaling and cell survival upon such stimuli. We also establish that KAT5 tyrosine phosphorylation is mediated by the tyrosine kinase c-Abl, thus revealing how this kinase affects early steps in the DDR and broadening its potential as a drug target for cancer therapy. KAT5 tyrosine phosphorylation upon DNA damageAs KAT5 binding to H3K9me3 promotes ATM activation 12 , we explored the potential regulation of the KAT5-H3K9me3 interaction. Thus, we purified KAT5 from human cells stably expressing Flag-tagged KAT5 before or after they had been treated with ionizing radiation (IR; Fig. 1a). As expected, when we tested the protein preparations in peptide binding studies, KAT5 bound an H3K9me3 peptide (M) more effectively than the corresponding unmethylated peptide (U; Fig. 1b, lanes 1 and 2). Strikingly, these studies Supplementary Fig. 1, KAT5 failed to bind detectably to peptides corresponding to the histone H3 methylation marks H3K4me3 and H3K27me3). Moreover, enhanced binding to the H3...

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Section: Discussionsupporting

confidence: 80%

Section: Discussionmentioning

confidence: 99%

Section: C-abl Targets Kat5 Tyr-44 To Promote Atm-mediated Signalingmentioning

confidence: 99%

See 1 more Smart Citation

KAT5 tyrosine phosphorylation couples chromatin sensing to ATM signalling

Kaidi

Jackson

2013

Nature

150

175

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“…These disparate responses to the same stimulus should not be very surprising because similar phenomena have been observed with other anti-cancer treatments. For example, radiation triggers anti-cancer p53 pathway and also cancer-promoting NF-κB and c-Abl (48, 49). In this case and in the case of Hsp70 depletion, the net effect is anti-cancerous.…”

Section: Discussionmentioning

confidence: 99%

Hsp70–Bag3 Interactions Regulate Cancer-Related Signaling Networks

et al. 2014

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Bag3, a nucleotide exchange factor of the heat shock protein Hsp70, has been implicated in cell signaling. Here we report that Bag3 interacts with the SH3 domain of Src, thereby mediating the effects of Hsp70 on Src signaling. Using several complementary approaches, we established that the Hsp70-Bag3 module is a broad-acting regulator of cancer cell signaling, including by modulating the activity of the transcription factors NF-kB, FoxM1 and Hif1α, the translation regulator HuR and the cell cycle regulators p21 and survivin. We also identified a small molecule inhibitor, YM-1, that disrupts Hsp70-Bag3 interaction. YM-1 mirrored the effects of Hsp70 depletion on these signaling pathways, and in vivo administration of this drug was sufficient to suppress tumor growth in mice. Overall, our results defined Bag3 as a critical factor in Hsp70-modulated signaling and offered a preclinical proof-of-concept that the Hsp70-Bag3 complex may offer an appealing anti-cancer target.

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“…c-Abl is activated by DNA damage, and subsequently amplifies the response by phosphorylating down-stream DNA damage proteins, including RAD51 the key enzyme for homology search in the HR process (31–33). In the context of synergy with CNDAC, inhibition of c-Abl by imatinib likely disables its contribution to this aspect of HR, thereby decreasing the possibility that CNDAC generated DSBs will be repaired.…”

Section: Discussionmentioning

confidence: 99%

Mechanism-Based Drug Combinations with the DNA Strand–Breaking Nucleoside Analog CNDAC

Liu

Jiang

Nowak

et al. 2016

Molecular Cancer Therapeutics

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CNDAC (2’-C-cyano-2’-deoxy-1-β-D-arabino-pentofuranosyl-cytosine, DFP10917) and its orally bioavailable prodrug, sapacitabine, are undergoing clinical trials for hematological malignancies and solid tumors. The unique action mechanism of inducing DNA strand breaks distinguishes CNDAC from other deoxycytidine analogs. To optimize the clinical potentials of CNDAC, we explored multiple strategies combining CNDAC with chemotherapeutic agents targeting distinct DNA damage repair pathways that are currently in clinical use. The ability of each agent to decrease proliferative potential, determined by clonogenic assays, was determined in paired cell lines proficient and deficient in certain DNA repair proteins. Subsequently each agent was used in combination with CNDAC at fixed concentration ratios. The clonogenicity was quantitated by median effect analysis, and a combination index was calculated. The c-Abl kinase inhibitor, imatinib, had synergy with CNDAC in HCT116 cells, regardless of p53 status. Inhibitors of PARP1 that interfere with homologous recombination (HR) repair or base excision repair (BER) and agents such as temozolomide that cause DNA damage repaired by the BER pathway were also synergistic with CNDAC. The toxicity of the nitrogen mustards, bendamustine and cytoxan, or of platinum compounds, which generate DNA adducts repaired by nucleotide excision repair and HR, was additive with CNDAC. An additive cell killing was also achieved by the combination of CNDAC with taxane mitotic inhibitors (paclitaxel and docetaxel). At concentrations which allow survival of the majority of wild type cells, the synergistic or additive combination effects were selective in HR-deficient cells. This study provides mechanistic rationales for combining CNDAC with other active drugs.

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c-Abl tyrosine kinase in the DNA damage response: cell death and more

Cited by 38 publications

References 22 publications

KAT5 tyrosine phosphorylation couples chromatin sensing to ATM signalling

KAT5 tyrosine phosphorylation couples chromatin sensing to ATM signalling

Hsp70–Bag3 Interactions Regulate Cancer-Related Signaling Networks

Mechanism-Based Drug Combinations with the DNA Strand–Breaking Nucleoside Analog CNDAC

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