The mTOR–S6K pathway links growth signalling to DNA damage response by targeting RNF168

Xie, Xu; Hu, Hongli; Tong, Xinyuan; Li, Long; Lei, Yu; Chen, Min; Yuan, Huairui; Xie, Xing; Li, Qingrun; Zhang, Yuxue; Ouyang, Han; Wei, Mengqi; Huang, Jing; Liu, Pengda; Gan, Wenjian; Liu, Yong; Xie, Anyong; Kuai, Xiaoling; Chirn, Gung-Wei; Zhou, Hu; Zeng, Rong; Hu, Ronggui; Qin, Jun; Meng, Fei-Long; Wei, Wenyi; Ji, Hongbin; Gao, Daming

doi:10.1038/s41556-017-0033-8

Cited by 99 publications

(92 citation statements)

References 53 publications

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“…Furthermore, mTORC1-dependent phosphorylation of the transcription factor TFEB promotes association of TFEB with members of the 14-3-3 family of proteins, thereby forcing its retention in the cytosol (88). However, the network connecting the mTOR pathway to the DNA damage response continues to be elucidated (92)(93)(94)(95). A recent study (95) showed that mTOR/S6K signaling leads to phosphorylation and subsequent degradation of RNF168, and hyperactivation of mTOR via LKB1 leads to decreased levels of RNF168 and increases DNA damage.…”

Section: Discussionmentioning

confidence: 99%

“…However, the network connecting the mTOR pathway to the DNA damage response continues to be elucidated (92)(93)(94)(95). A recent study (95) showed that mTOR/S6K signaling leads to phosphorylation and subsequent degradation of RNF168, and hyperactivation of mTOR via LKB1 leads to decreased levels of RNF168 and increases DNA damage. One possible explanation for our observed results is that mTOR (or one of its downstream targets) could directly phosphorylate polκ and thereby affect its localization as has been shown for other proteins that undergo nuclear-cytoplasmic shuttling (96)(97)(98)(99).…”

Section: Discussionmentioning

confidence: 99%

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Regulation of the error-prone DNA polymerase polκ by oncogenic signaling and its contribution to drug resistance

Temprine¹,

Langdon

Mehta

et al. 2018

Preprint

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AbstractMutations in the proofreading domains of the replicative DNA polymerases polδ and polε are associated with elevated mutation rates in cancer, but the roles of other DNA polymerases in tumorigenesis remain poorly understood. One such polymerase is polκ, an enzyme that plays a key role in translesion synthesis. polκ contributes to cell survival in the face of DNA damage but can be highly mutagenic due to lack of a proofreading domain. Here we demonstrate that cancer cells under stress from oncogene inhibition upregulate polκ and shift its localization from the cytoplasm to the nucleus. This effect can be phenocopied by mTOR inhibition or glucose deprivation, analogous to stress-induced mutagenesis in E. coli whereby cell stress and nutrient deprivation can upregulate and activate DinB/pol IV (the bacterial orthologue of polκ). We find that cancer cells normally sequester polκ in the cytoplasm via exportin-1, likely to prevent excess mutagenesis from the error-prone nature of this polymerase. Subverting the normal nuclear-cytoplasmic shuttling by forced overexpression of nuclear polκ increases resistance of melanoma cells to the BRAFV600E inhibitor vemurafenib. This data suggests a mechanism by which cancer cells regulate the expression and localization of the error-prone polymerase polκ, abrogation of which can contribute to drug resistance.One Sentence Summary: Cancer cells under stress from oncogene or mTOR inhibition dysregulate the error-prone DNA polymerase polκ, which contributes to drug resistance in melanoma cells.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Regulation of the error-prone DNA polymerase polκ by oncogenic signaling and its contribution to drug resistance

Temprine¹,

Langdon

Mehta

et al. 2018

Preprint

View full text Add to dashboard Cite

show abstract

“…Our recent study has demonstrated that mTORC1-S6K pathway can inhibit DDR through phosphorylating RNF168 at Ser60 by impairing its E3 ligase activity and promoting TRIP12-dependent RNF168 degradation. Importantly, ectopic expression of phosphorylation-resistant mutant, RNF168-S60A, rescues DNA damage defects and inhibits Lkb1 deletion (causing hyper-activation of mTORC1-S6K pathway)-induced lung tumor development (Xie et al 2018) (Fig. 1b).…”

Section: Mtor Signaling and Ddrmentioning

confidence: 98%

Crosstalk between signaling pathways and DNA damage response

Wang

Zhang

et al. 2019

GENOME INSTAB. DIS.

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Living organisms have developed a complex signaling system to sense diverse growth signals and co-ordinate intracellular bioprocesses, so that they survive in various conditions. Since organisms are often exposed to environmental and genomic threats which cause DNA damages, DNA damage response (DDR) and repair systems are important for maintenance of genome stability and integrity. A line of evidences has demonstrated that there is tight crosstalk between growth signaling pathways and DDR systems. In this review, we give a brief overview of recent reports dissecting the interaction between signaling pathways and DDR at molecular level, which may further expand the knowledge of the signaling network and provide clues for disease therapy.

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“…Hyperactivation of TORC1 has been linked to defects in the DNA damage response in single celled and multicellular organisms (Begley, Rosenbach, Ideker, & Samson, 2004;Feng et al, 2007;Klermund, Bender, & Luke, 2014;Ma, Vassetzky, & Dokudovskaya, 2018;Pai et al, 2016;Xie et al, 2018). The observation that meiotic DSBs promote the GATOR1 dependent downregulation of TORC1 activity during Drosophila oogenesis, suggested the low TORC1 activity may be important to the regulation of meiotic DSB.…”

Section: Gator1 and Tsc Promote The Repair Of Meiotic Dsbsmentioning

confidence: 99%

The GATOR complex regulates an essential response to meiotic double-stranded breaks inDrosophila

Wei

Bettedi

Kim

et al. 2018

Preprint

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The TORC1 inhibitor GATOR1/SEACIT controls meiotic entry and early meiotic events in yeast. However, how metabolic pathways influence meiotic progression in metazoans remains poorly understood. Here we report that the TORC1 regulators GATOR1 and GATOR2 mediate a response to meiotic double-stranded breaks (DSBs) during Drosophila oogenesis. We find that meiotic DSBs trigger the activation of a GATOR1 dependent pathway that downregulates TORC1 activity in the female germline. In GATOR1 mutants, high TORC1 activity results in the delayed repair of meiotic DSBs and the hyperactivation of p53. Conversely, the GATOR2 component Mio is required to attenuate GATOR1 activity, to ensure that meiotic DSBs do not trigger a permanent growth arrest. Unexpectedly, we found that GATOR1 inhibits retrotransposon expression in the presence of meiotic DSBs in a pathway that functions in parallel to p53. Our studies have revealed a link between the GATOR complex, the repair of meiotic DSBs and retrotransposon expression

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The mTOR–S6K pathway links growth signalling to DNA damage response by targeting RNF168

Cited by 99 publications

References 53 publications

Regulation of the error-prone DNA polymerase polκ by oncogenic signaling and its contribution to drug resistance

Regulation of the error-prone DNA polymerase polκ by oncogenic signaling and its contribution to drug resistance

Crosstalk between signaling pathways and DNA damage response

The GATOR complex regulates an essential response to meiotic double-stranded breaks inDrosophila

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