TOR Signaling Is a Determinant of Cell Survival in Response to DNA Damage

Shen, Changxian; Lancaster, Cynthia S.; Shi, Bin; Guo, Hong; Padma, T.; Bjornsti, Mary-Ann

doi:10.1128/mcb.00290-07

Cited by 86 publications

(85 citation statements)

References 48 publications

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“…Previously, Rnr3, another subunit of RNR has been implicated in MMS-induced mutation. Specifically, the inhibition of the TORC1 pathway, which controls transcription of RNR3 via Rad53, also results in a reduction of mutation in response to MMS [49]. These data suggest that the effect on induced mutation may be generalized to other subunits of the RNR complex.…”

Section: Nih-pa Author Manuscriptmentioning

confidence: 69%

Identification of pathways controlling DNA damage induced mutation in Saccharomyces cerevisiae

Lis¹,

O'Neill²,

Gil-Lamaignere³

et al. 2008

DNA Repair

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Mutation in response to most types of DNA damage is thought to be mediated by the error-prone sub-branch of post-replication repair and the associated translesion synthesis polymerases. To further understand the mutagenic response to DNA damage, we screened a collection of 4848 haploid gene deletion strains of Saccharomyces cerevisiae for decreased damage-induced mutation of the CAN1 gene. Through extensive quantitative validation of the strains identified by the screen, we identified ten genes, which included error-prone post-replication repair genes known to be involved in induced mutation, as well as two additional genes, FYV6 and RNR4. We demonstrate that FYV6 and RNR4 are epistatic with respect to induced mutation, and that they function, at least partially, independently of post-replication repair. This pathway of induced mutation appears to be mediated by an increase in dNTP levels that facilitates lesion bypass by the replicative polymerase Polδ, and it is as important as error-prone post-replication repair in the case of UV-and MMS-induced mutation, but solely responsible for EMS-induced mutation. We show that Rnr4/Polδ-induced mutation is efficiently inhibited by hydroxyurea, a small molecule inhibitor of ribonucleotide reductase, suggesting that if similar pathways exist in human cells, intervention in some forms of mutation may be possible. Keywordsyeast; post-replication repair; induced mutagenesis 1.IntroductionThe stability of the genome is critical for life, but mutation occurs as a result of both exogenous and endogeneous mutagens [1]. Mutations contribute to ageing [2], oncogenesis, tumor progression [3][4][5], and resistance to chemotherapy [6][7][8]. Ironically, because many chemotherapeutic drugs are mutagens, they may themselves play a role in inducing the mutations that give rise to resistance and therapy failure [9][10][11].For many years, it was assumed that mutagens induced DNA damage, and the damaged DNA caused the replicative polymerases to make errors during DNA replication. However, it is now understood that most types of DNA damage inhibit DNA replication, and that the cellular response to this inhibition is critical for the induction of mutation. The cellular response to replication blocks in the yeast Saccharomyces cerevisiae has been intensively studied and is 1Corresponding author Floyd E. Romesberg, Department of Chemistry, The Scripps Research Institute, CB262R, 10550 N. Torrey Pines Rd, La Jolla, CA, 92037, Phone: (858) Fax: (858) 784-7472, E-mail: floyd@scripps.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Pub...

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Section: Nih-pa Author Manuscriptmentioning

confidence: 69%

Identification of pathways controlling DNA damage induced mutation in Saccharomyces cerevisiae

Lis¹,

O'Neill²,

Gil-Lamaignere³

et al. 2008

DNA Repair

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“…Anti-apoptotic Bcl-2 and FLIPs, which were up-regulated in the transition from two-dimensional to three-dimensional, were found to be independent of mTOR/ S6K activity, suggesting that they may account for resistance that is not controlled by mTOR/S6K, at least in two of the cell lines. mTOR may also contribute to survival in general by its support of metabolism and energy (56) or of protein translation, key functions to which the cells may become reliant or "addicted" (58).…”

Section: Discussionmentioning

confidence: 99%

“…8). mTOR has also been shown to associate with mitochondria (55) possibly serving as a modulator of stress signals (56) and cell fate (57). Although we were able to localize the resistance to the mitochondria, we were not able to identify a specific molecule that transduced the survival function of mTOR/S6K in spheroids.…”

Section: Discussionmentioning

confidence: 99%

Mammalian Target of Rapamycin Contributes to the Acquired Apoptotic Resistance of Human Mesothelioma Multicellular Spheroids

Barbone

Yang

Morgan

et al. 2008

Journal of Biological Chemistry

137

121

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When grown as three-dimensional structures, tumor cells can acquire an additional multicellular resistance to apoptosis that may mimic the chemoresistance found in solid tumors. We developed a multicellular spheroid model of malignant mesothelioma to investigate molecular mechanisms of acquired apoptotic resistance. We found that mesothelioma cell lines, when grown as multicellular spheroids, acquired resistance to a variety of apoptotic stimuli, including combinations of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), ribotoxic stressors, histone deacetylase, and proteasome inhibitors, that were highly effective against mesothelioma cells when grown as monolayers. Inhibitors of the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin (mTOR) pathway, particularly rapamycin, blocked much of the acquired resistance of the spheroids, suggesting a key role for mTOR. Knockdown by small interference RNA of S6K, a major downstream target of mTOR, reproduced the effect of rapamycin, thereby confirming the role of mTOR and of S6K in the acquired resistance of threedimensional spheroids. Rapamycin or S6K knockdown increased TRAIL-induced caspase-8 cleavage in spheroids, suggesting initially that mTOR inhibited apoptosis by actions at the death receptor pathway; however, isolation of the apoptotic pathways by means of Bid knockdown ablated this effect showing that mTOR actually controls a step distal to Bid, probably at the level of the mitochondria. In sum, mTOR and S6K contribute to the apoptotic resistance of mesothelioma cells in three-dimensional, not in twodimensional, cultures. The three-dimensional model may reflect a more clinically relevant in vitro setting in which mTOR exhibits anti-apoptotic properties.Resistance to apoptosis is a distinguishing characteristic of all tumors (1) and underlies their resistance to therapy (2). Understanding the molecular foundations of apoptotic resistance could lead to improvements in the utility of current therapies or provide new therapies altogether. In vitro, apoptotic resistance of tumor cells is usually studied using two-dimensional monolayers. However, cells can attain increased resistance when grown in three-dimensional structures, a phenomenon referred as the acquisition of multicellular resistance (3). This acquired property of tumor cells may help explain why promising findings from in vitro studies have not been easily translated into therapy (4). Consequently, in the last decade, multicellular spheroids have become a valuable tool in the study of solid tumors by representing a threedimensional system of intermediate cellular complexity between monolayer cell cultures and tumors in vivo (5, 6).Human malignant pleural mesothelioma, an aggressive thoracic cancer that arises from the pleural mesothelium, is characterized by a profound resistance to standard anti-neoplastic therapies. At present, no curative therapy is available (7). To investigate the apoptotic resistance of mesothelioma, we are increasingly utilizing in vitro three-dimension...

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“…The protein levels and activity of RNR are tightly controlled in all organisms because higher than physiological levels of dNTPs lead to gene mutations and lower levels compromise cell viability [40][41][42]. It was reported that rapamycin inhibition of TORC1 enhanced the cytotoxicity of DNA damage agents and at the same time reduced the DNA damage-induced mutations through downregulation of RNR in budding yeast, suggesting that the TOR pathway and DNA damage checkpoint function in parallel to control RNR in response to genotoxin [43]. The DNA damage-induced increase of dNTP levels is conserved in mammalian cells as one of the small subunits of mammalian RNR, p53R2, is induced by p53 following DNA damage [44].…”

Section: Tor Sustains Ribonucleotide Reductase In Response To Dna Damagementioning

confidence: 99%

Molecularly targeting the PI3K-Akt-mTOR pathway can sensitize cancer cells to radiotherapy and chemotherapy

Wang¹,

Huang²,

Zhang³

2014

Cellular and Molecular Biology Letters

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telangiectasia and Rad3-related; CDK4/6 -cyclin-dependent kinase 4/6; Chk1 -checkpoint kinase 1; Chk2 -checkpoint kinase 2; FA -Fanconi anemia; FANCD2 -Fanconi anemia group D2; FANCI -Fanconi anemia group I; HR -homologous recombination; ICL -DNA interstrand crosslinker; IGFBP-3 -insulin-like growth factor binding protein 3; IRS -insulin receptor substrate; MAPKmitogen-activated protein kinase; mTOR -mammalian target of rapamycin; NERnucleotide excision repair; PH -pleckstrin homology; PI3K -phosphoinositide 3-kinase; PIP2 -phosphatidylinositol 4,5-phosphate; PIP3 -phosphatidylinositol 3,4,5-trisphosphate; PTEN -phosphatase/tensin homolog deleted on chromosome 10; Rb -retinoblastoma; Rheb -Ras-homolog enriched in brain; RNR -ribonucleotide reductase; RTK -receptor tyrosine kinase; TLS -translesion DNA synthesis; TSC2 -tuberous sclerosis complex-2 Abstract: Radiotherapy and chemotherapeutic agents that damage DNA are the current major non-surgical means of treating cancer. However, many patients develop resistances to chemotherapy drugs in their later lives. The PI3K and Ras signaling pathways are deregulated in most cancers, so molecularly targeting PI3K-Akt or Ras-MAPK signaling sensitizes many cancer types to radiotherapy and chemotherapy, but the underlying molecular mechanisms have yet to be determined. During the multi-step processes of tumorigenesis, cancer cells gain the capability to disrupt the cell cycle checkpoint and increase the activity of CDK4/6 by disrupting the PI3K, Ras, p53, and Rb signaling circuits. Recent advances have demonstrated that PI3K-Akt-mTOR signaling controls FANCD2

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TOR Signaling Is a Determinant of Cell Survival in Response to DNA Damage

Cited by 86 publications

References 48 publications

Identification of pathways controlling DNA damage induced mutation in Saccharomyces cerevisiae

Identification of pathways controlling DNA damage induced mutation in Saccharomyces cerevisiae

Mammalian Target of Rapamycin Contributes to the Acquired Apoptotic Resistance of Human Mesothelioma Multicellular Spheroids

Molecularly targeting the PI3K-Akt-mTOR pathway can sensitize cancer cells to radiotherapy and chemotherapy

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