Nuclear Tau, p53 and Pin1 Regulate PARN-Mediated Deadenylation and Gene Expression

Baquero, Jorge; Varriano, Sophia; Ordóñez, Martha; Kuczaj, Pawel; Murphy, Michael R.; Aruggoda, Gamage; Lundine, Devon; Morozova, Viktoriya; Makki, Ali El-Hadi; Alonso, Alejandra; Kleiman, Frida E.

doi:10.3389/fnmol.2019.00242

Cited by 23 publications

(23 citation statements)

References 92 publications

(243 reference statements)

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“…Genetic alteration of P53 variants affects aging, cognitive decline, and TAU phosphorylation in mice [ 151 , 152 ]. Recently it has been found that P53 is part of a complex containing nuclear TAU, PIN1 and the polyA-specific ribonuclease PARN in the colon cancer cell line HCT116 [ 153 ], which are also rich in hyperphosphorylated TAU forms [ 154 ]. PARN-mediated nuclear deadenylation is activated by TAU, further potentiated by P53 and reduced by TAU phosphorylation.…”

Section: Possible Microtubules-independent Pathways Explaining Thementioning

confidence: 99%

Emerging Evidences for an Implication of the Neurodegeneration-Associated Protein TAU in Cancer

Papin

Paganetti

2020

Brain Sciences

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Neurodegenerative disorders and cancer may appear unrelated illnesses. Yet, epidemiologic studies indicate an inverse correlation between their respective incidences for specific cancers. Possibly explaining these findings, increasing evidence indicates that common molecular pathways are involved, often in opposite manner, in the pathogenesis of both disease families. Genetic mutations in the MAPT gene encoding for TAU protein cause an inherited form of frontotemporal dementia, a neurodegenerative disorder, but also increase the risk of developing cancer. Assigning TAU at the interface between cancer and neurodegenerative disorders, two major aging-linked disease families, offers a possible clue for the epidemiological observation inversely correlating these human illnesses. In addition, the expression level of TAU is recognized as a prognostic marker for cancer, as well as a modifier of cancer resistance to chemotherapy. Because of its microtubule-binding properties, TAU may interfere with the mechanism of action of taxanes, a class of chemotherapeutic drugs designed to stabilize the microtubule network and impair cell division. Indeed, a low TAU expression is associated to a better response to taxanes. Although TAU main binding partners are microtubules, TAU is able to relocate to subcellular sites devoid of microtubules and is also able to bind to cancer-linked proteins, suggesting a role of TAU in modulating microtubule-independent cellular pathways associated to oncogenesis. This concept is strengthened by experimental evidence linking TAU to P53 signaling, DNA stability and protection, processes that protect against cancer. This review aims at collecting literature data supporting the association between TAU and cancer. We will first summarize the evidence linking neurodegenerative disorders and cancer, then published data supporting a role of TAU as a modifier of the efficacy of chemotherapies and of the oncogenic process. We will finish by addressing from a mechanistic point of view the role of TAU in de-regulating critical cancer pathways, including the interaction of TAU with cancer-associated proteins.

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Section: Possible Microtubules-independent Pathways Explaining Thementioning

confidence: 99%

Emerging Evidences for an Implication of the Neurodegeneration-Associated Protein TAU in Cancer

Papin

Paganetti

2020

Brain Sciences

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“…More specifically, phosphorylation of nuclear tau negatively regulates its nuclear function in pluripotent neuronal cells and neuroblastoma cells 10 . Previous studies have revealed that nuclear tau plays a role in the DNA damage response (DDR) through deadenylation, which triggers major mRNA decay pathways 11,12 . Most recently, we found that oligomeric assemblies of tau containing RNA-binding proteins impair chromatin remodeling and nuclear lamina formation through associations with histones and chromatin components in the nuclear compartment 13 .…”

Section: Introductionmentioning

confidence: 99%

Tau modulates mRNA transcription, alternative polyadenylation profiles of hnRNPs, chromatin remodeling and spliceosome complexes

Montalbano

Jaworski

Garcia

et al. 2021

Preprint

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Tau protein is a known contributor in several neurodegenerative diseases, including Alzheimer ’s disease (AD) and frontotemporal dementia (FTD). It is well-established that tau forms pathological aggregates and fibrils in these diseases. Tau has been observed within the nuclei of neurons, but there is a gap in understanding regarding the mechanism by which tau modulates transcription. We are interested in the P301L mutation of tau, which has been associated with FTD and increased tau aggregation. Our study utilized tau-inducible HEK (iHEK) cells to reveal that WT and P301L tau distinctively alter the transcription and alternative polyadenylation (APA) profiles of numerous nuclear precursors mRNAs, which then translate to form proteins involved in chromatin remodeling and splicing. We isolated total mRNA before and after over-expressing tau and then performed Poly(A)-ClickSeq (PAC-Seq) to characterize mRNA expression and APA profiles. We characterized changes in Gene Ontology (GO) pathways using EnrichR and Gene Set Enrichment Analysis (GSEA). We observed that P301L tau up-regulates genes associated with reactive oxygen species responsiveness as well as genes involved in dendrite, microtubule, and nuclear body/speckle formation. The number of genes regulated by WT tau is greater than the mutant form, which indicates that the P301L mutation causes loss-of-function at the transcriptional level. WT tau up-regulates genes contributing to cytoskeleton-dependent intracellular transport, microglial activation, microtubule and nuclear chromatin organization, formation of nuclear bodies and speckles. Interestingly, both WT and P301L tau commonly down-regulate genes responsible for ubiquitin-proteosome system. In addition, WT tau significantly down-regulates several genes implicated in chromatin remodeling and nucleosome organization. Although there are limitations inherent to the model systems used, this study will improve understanding regarding the nuclear impact of tau at the transcriptional and post-transcriptional level. This study also illustrates the potential impact of P301L tau on the human brain genome during early phases of pathogenesis.

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“…HuR occupies ARE to release NCL, p53, and PARN, and thereby stabilizes the p53 mRNA (X. Zhang et al, 2018). The activated p53 can bind with PARN and enhance its deadenylation activity towards nonessential transcripts (Devany et al, 2013), probably through a nuclear complex containing activated p53, tau, a tau‐binding protein Pin1, and PARN (Baquero et al, 2019). Therefore, PARN is involved in multiple feedback loops to control p53 mRNA and protein levels.…”

Section: Parn In Ddr and Genomic Stabilitymentioning

confidence: 99%

Diverse functions of deadenylases in DNA damage response and genomic integrity

Yan

2020

WIREs RNA

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DNA damage response (DDR) is a coordinated network of diverse cellular processes including the detection, signaling, and repair of DNA lesions, the adjustment of metabolic network and cell fate determination. To deal with the unavoidable DNA damage caused by either endogenous or exogenous stresses, the cells need to reshape the gene expression profile to allow efficient transcription and translation of DDR‐responsive messenger RNAs (mRNAs) and to repress the nonessential mRNAs. A predominant method to adjust RNA fate is achieved by modulating the 3′‐end oligo(A) or poly(A) length via the opposing actions of polyadenylation and deadenylation. Poly(A)‐specific ribonuclease (PARN) and the carbon catabolite repressor 4 (CCR4)‐Not complex, the major executors of deadenylation, are indispensable to DDR and genomic integrity in eukaryotic cells. PARN modulates cell cycle progression by regulating the stabilities of mRNAs and microRNA (miRNAs) involved in the p53 pathway and contributes to genomic stability by affecting the biogenesis of noncoding RNAs including miRNAs and telomeric RNA. The CCR4‐Not complex is involved in diverse pathways of DDR including transcriptional regulation, signaling pathways, mRNA stabilities, translation regulation, and protein degradation. The RNA targets of deadenylases are tuned by the DDR signaling pathways, while in turn the deadenylases can regulate the levels of DNA damage‐responsive proteins. The mutual feedback between deadenylases and the DDR signaling pathways allows the cells to precisely control DDR by dynamically adjusting the levels of sensors and effectors of the DDR signaling pathways. Here, the diverse functions of deadenylases in DDR are summarized and the underlying mechanisms are proposed according to recent findings. This article is categorized under: RNA Processing > 3' End Processing RNA in Disease and Development > RNA in Disease RNA Turnover and Surveillance > Turnover/Surveillance Mechanisms

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Nuclear Tau, p53 and Pin1 Regulate PARN-Mediated Deadenylation and Gene Expression

Cited by 23 publications

References 92 publications

Emerging Evidences for an Implication of the Neurodegeneration-Associated Protein TAU in Cancer

Emerging Evidences for an Implication of the Neurodegeneration-Associated Protein TAU in Cancer

Tau modulates mRNA transcription, alternative polyadenylation profiles of hnRNPs, chromatin remodeling and spliceosome complexes

Diverse functions of deadenylases in DNA damage response and genomic integrity

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