ATM-dependent E2F1 accumulation in the nucleolus is an indicator of ribosomal stress in early response to DNA damage

Jin, Yichen; An, Guo-Shun; Ni, Jing; Li, Shuyan; Jia, Hong-Ti

doi:10.4161/cc.28605

Cited by 11 publications

(10 citation statements)

References 48 publications

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“…In addition, transcription factor E2F1 promotes G1/S transition and induces apoptosis by controlling target gene expression [ 35 ]. We have previously shown that E2F1 is induced in H1299 cells during DDR [ 36 , 37 ]. E2F1 may therefore counteract p21-inhibited G1/S transition, promoting S phase cells and apoptosis in H1299 cells.…”

Section: Discussionmentioning

confidence: 99%

“…However, E2F1 cannot achieve that in A549 cells, because p53 may counteract E2F1 effect by association with it [ 38 ]. Contrarily, the early nucleolar accumulation of E2F1 may release p53 function [ 36 ] to activate p21 and p53R2 genes and p53-dependent DNA repair in A549 cells. Indeed, A549 cells displayed a partial capability of recovering DNA replication at late time of 8-Cl-Ado exposure, but H1299 cells could not ( Figure 6 ).…”

Section: Discussionmentioning

confidence: 99%

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DNA Damage-Response Pathway Heterogeneity of Human Lung Cancer A549 and H1299 Cells Determines Sensitivity to 8-Chloro-Adenosine

Yang

et al. 2018

IJMS

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Human lung cancer H1299 (p53-null) cells often display enhanced susceptibility to chemotherapeutics comparing to A549 (p53-wt) cells. However, little is known regarding to the association of DNA damage-response (DDR) pathway heterogeneity with drug sensitivity in these two cells. We investigated the DDR pathway differences between A549 and H1299 cells exposed to 8-chloro-adenosine (8-Cl-Ado), a potential anticancer drug that can induce DNA double-strand breaks (DSBs), and found that the hypersensitivity of H1299 cells to 8-Cl-Ado is associated with its DSB overaccumulation. The major causes of excessive DSBs in H1299 cells are as follows: First, defect of p53-p21 signal and phosphorylation of SMC1 increase S phase cells, where replication of DNA containing single-strand DNA break (SSB) produces more DSBs in H1299 cells. Second, p53 defect and no available induction of DNA repair protein p53R2 impair DNA repair activity in H1299 cells more severely than A549 cells. Third, cleavage of PARP-1 inhibits topoisomerase I and/or topoisomerase I-like activity of PARP-1, aggravates DNA DSBs and DNA repair mechanism impairment in H1299 cells. Together, DDR pathway heterogeneity of cancer cells is linked to cancer susceptibility to DNA damage-based chemotherapeutics, which may provide aid in design of chemotherapy strategy to improve treatment outcomes.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

DNA Damage-Response Pathway Heterogeneity of Human Lung Cancer A549 and H1299 Cells Determines Sensitivity to 8-Chloro-Adenosine

Yang

et al. 2018

IJMS

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“…Subsequently, both p53 and E2F1 participate in DNA damage-induced apoptosis: p53 activates transcription of Bax, Puma, Noxa and several other pro-apoptotic genes, whereas E2F1 switches from activation of cell cycle genes to pro-apoptotic TP73 gene [ 38 – 40 ]. Furthermore, both p53 and E2F1 when phosphorylated by ATM can be found at DNA damage foci, suggesting that they can physically recruit DNA repair proteins [ 41 , 42 ]. One of the critical regulators for both p53 and E2F1 is an E3 ubiquitin ligase, Mdm2.…”

Section: Introductionmentioning

confidence: 99%

KMT Set7/9 affects genotoxic stress response via the Mdm2 axis

et al. 2015

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Genotoxic stress inflicted by anti-cancer drugs causes DNA breaks and genome instability. DNA double strand breaks induced by irradiation or pharmacological inhibition of Topoisomerase II activate ATM (ataxia-telangiectasia-mutated) kinase signalling pathway that in turn triggers cell cycle arrest and DNA repair. ATM-dependent gamma-phosphorylation of histone H2Ax and other histone modifications, including ubiquitnylation, promote exchange of histones and recruitment of DNA damage response (DDR) and repair proteins. Signal transduction pathways, besides DDR itself, also control expression of genes whose products cause cell cycle arrest and/or apoptosis thus ultimately affecting the sensitivity of cells to genotoxic stress. In this study, using a number of experimental approaches we provide evidence that lysine-specific methyltransferase (KMT) Set7/9 affects DDR and DNA repair, at least in part, by regulating the expression of an E3 ubiquitin ligase, Mdm2. Furthermore, we show that Set7/9 physically interacts with Mdm2. Several cancer cell lines with inverse expression of Set7/9 and Mdm2 displayed diminished survival in response to genotoxic stress. These findings are signified by our bioinformatics studies suggesting that the unleashed expression of Mdm2 in cancer patients with diminished expression of Set7/9 is associated with poor survival outcome.

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“…p53 is known to be regulated by nucleoli those function is directly dependent on its structure (Boyd et al, 2011). As a consequence, damage in rDNA genes could indirectly result in the activation of p53 leading to cell cycle arrest or apoptosis (Jin et al, 2014). consequences.…”

Section: Resultsmentioning

confidence: 99%

Parental exposure to environmental concentrations of diuron leads to aneuploidy in embryos of the Pacific oyster, as evidenced by fluorescent in situ hybridization

et al. 2015

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Changes in normal chromosome numbers (i.e. aneuploidy) due to abnormal chromosome segregation may arise either spontaneously or as a result of chemical/radiation exposure, particularly during cell division. Coastal ecosystems are continuously subjected to various contaminants originating from urban, industrial and agricultural activities. Genotoxicity is common to several families of major environmental pollutants, including pesticides, which therefore represent a potential important environmental hazard for marine organisms. A previous study demonstrated the vertical transmission of DNA damage by subjecting oyster genitors to short-term exposure to the herbicide diuron at environmental concentrations during gametogenesis. In this paper, Fluorescent in situ hybridization (FISH) was used to further characterize diuron-induced DNA damage at the chromosomal level. rDNA genes (5S and 18-5.8-28S), previously mapped onto Crassostrea gigas chromosomes 4, 5 and 10, were used as probes on the interphase nuclei of embryo preparations. Our results conclusively show higher aneuploidy (hypo- or hyperdiploidy) level in embryos from diuron-exposed genitors, with damage to the three studied chromosomal regions. This study suggests that sexually developing oysters are vulnerable to diuron exposure, incurring a negative impact on reproductive success and oyster recruitment.

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ATM-dependent E2F1 accumulation in the nucleolus is an indicator of ribosomal stress in early response to DNA damage

Cited by 11 publications

References 48 publications

DNA Damage-Response Pathway Heterogeneity of Human Lung Cancer A549 and H1299 Cells Determines Sensitivity to 8-Chloro-Adenosine

DNA Damage-Response Pathway Heterogeneity of Human Lung Cancer A549 and H1299 Cells Determines Sensitivity to 8-Chloro-Adenosine

KMT Set7/9 affects genotoxic stress response via the Mdm2 axis

Parental exposure to environmental concentrations of diuron leads to aneuploidy in embryos of the Pacific oyster, as evidenced by fluorescent in situ hybridization

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