PTEN Controls the DNA Replication Process through MCM2 in Response to Replicative Stress

Feng, Jiawen; Liang, Jing; Li, Jiaju; Li, Yunqiao; Liang, Hui; Zhao, Xuyang; McNutt, Michael A.; Yin, Yuxin

doi:10.1016/j.celrep.2015.10.016

Cited by 52 publications

(51 citation statements)

References 49 publications

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“…Interestingly, PTEN has been shown to directly control the function of the DNA replication factor MCM2 during DNA replication stress [51]. Replication stress occurs at the rDNA and has been reported as a potent driver of functional decline in HSCs [52].…”

Section: Discussionmentioning

confidence: 99%

Ribosomal DNA copy number loss and sequence variation in cancer

et al. 2017

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Ribosomal DNA is one of the most variable regions in the human genome with respect to copy number. Despite the importance of rDNA for cellular function, we know virtually nothing about what governs its copy number, stability, and sequence in the mammalian genome due to challenges associated with mapping and analysis. We applied computational and droplet digital PCR approaches to measure rDNA copy number in normal and cancer states in human and mouse genomes. We find that copy number and sequence can change in cancer genomes. Counterintuitively, human cancer genomes show a loss of copies, accompanied by global copy number co-variation. The sequence can also be more variable in the cancer genome. Cancer genomes with lower copies have mutational evidence of mTOR hyperactivity. The PTEN phosphatase is a tumor suppressor that is critical for genome stability and a negative regulator of the mTOR kinase pathway. Surprisingly, but consistent with the human cancer genomes, hematopoietic cancer stem cells from a Pten-/- mouse model for leukemia have lower rDNA copy number than normal tissue, despite increased proliferation, rRNA production, and protein synthesis. Loss of copies occurs early and is associated with hypersensitivity to DNA damage. Therefore, copy loss is a recurrent feature in cancers associated with mTOR activation. Ribosomal DNA copy number may be a simple and useful indicator of whether a cancer will be sensitive to DNA damaging treatments.

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Section: Discussionmentioning

confidence: 99%

Ribosomal DNA copy number loss and sequence variation in cancer

et al. 2017

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“…We establish a requirement for PTEN protein phosphatase activity, but not its lipid phosphatase activity, in ICL repair. PTEN has recently been shown to dephosphorylate MCM2 S41 and PLK1 T2105051, and both of these mechanisms are likely to contribute to the observed phenotypes of PTEN −/− cells. Dephosphorylation of MCM2 S41 prevents replication fork progression under conditions of replication stress50.…”

Section: Discussionmentioning

confidence: 99%

“…PTEN has recently been shown to dephosphorylate MCM2 S41 and PLK1 T2105051, and both of these mechanisms are likely to contribute to the observed phenotypes of PTEN −/− cells. Dephosphorylation of MCM2 S41 prevents replication fork progression under conditions of replication stress50. ICLs are well known to pose a potent block to replication fork progression52.…”

Section: Discussionmentioning

confidence: 99%

The PTEN phosphatase functions cooperatively with the Fanconi anemia proteins in DNA crosslink repair

Vuono

Mukherjee

Vierra

et al. 2016

Sci Rep

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Fanconi anemia (FA) is a genetic disease characterized by bone marrow failure and increased cancer risk. The FA proteins function primarily in DNA interstrand crosslink (ICL) repair. Here, we have examined the role of the PTEN phosphatase in this process. We have established that PTEN-deficient cells, like FA cells, exhibit increased cytotoxicity, chromosome structural aberrations, and error-prone mutagenic DNA repair following exposure to ICL-inducing agents. The increased ICL sensitivity of PTEN-deficient cells is caused, in part, by elevated PLK1 kinase-mediated phosphorylation of FANCM, constitutive FANCM polyubiquitination and degradation, and the consequent inefficient assembly of the FA core complex, FANCD2, and FANCI into DNA repair foci. We also establish that PTEN function in ICL repair is dependent on its protein phosphatase activity and ability to be SUMOylated, yet is independent of its lipid phosphatase activity. Finally, via epistasis analysis, we demonstrate that PTEN and FANCD2 function cooperatively in ICL repair.

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“…PTEN also accumulates in the cell nucleus through passive diffusion, Ran-MVP-mediated transport and mono-ubiquitination-regulated mechanisms9. In the nucleus, PTEN maintains genome integrity and regulates the process of DNA replication through regulation of RPA1, MCM2 and TOP2A (refs 10, 11, 12, 13). In addition to its tumour suppressor function, PTEN is also involved in embryonic development, lipid metabolism1415, Alzheimer's disease16 and antiviral innate immunity17.…”

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confidence: 99%

PTENβ is an alternatively translated isoform of PTEN that regulates rDNA transcription

et al. 2017

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PTEN is a critical tumour suppressor that is frequently mutated in human cancer. We have previously identified a CUG initiated PTEN isoform designated PTENα, which functions in mitochondrial bioenergetics. Here we report the identification of another N-terminal extended PTEN isoform, designated PTENβ. PTENβ translation is initiated from an AUU codon upstream of and in-frame with the AUG initiation sequence for canonical PTEN. We show that the Kozak context and a downstream hairpin structure are critical for this alternative initiation. PTENβ localizes predominantly in the nucleolus, and physically associates with and dephosphorylates nucleolin, which is a multifunctional nucleolar phosphoprotein. Disruption of PTENβ alters rDNA transcription and promotes ribosomal biogenesis, and this effect can be reversed by re-introduction of PTENβ. Our data show that PTENβ regulates pre-rRNA synthesis and cellular proliferation. These results demonstrate the complexity of the PTEN protein family and the diversity of its functions.

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PTEN Controls the DNA Replication Process through MCM2 in Response to Replicative Stress

Cited by 52 publications

References 49 publications

Ribosomal DNA copy number loss and sequence variation in cancer

Ribosomal DNA copy number loss and sequence variation in cancer

The PTEN phosphatase functions cooperatively with the Fanconi anemia proteins in DNA crosslink repair

PTENβ is an alternatively translated isoform of PTEN that regulates rDNA transcription

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