Tau affects P53 function and cell fate during the DNA damage response

Abstract Cells are constantly exposed to DNA damaging insults. To protect the organism, cells developed a complex molecular response coordinated by P53, the master regulator of DNA repair, cell division and cell fate. DNA damage accumulation and abnormal cell fate decision may represent a pathomechanism shared by aging-associated disorders such as cancer and neurodegeneration. Here, we examined this hypothesis in the context of tauopathies, a neurodegenerative disorder group characterized by Tau protein deposition. For this, the response to an acute DNA damage was studied in neuroblastoma cells with depleted Tau, as a model of loss-of-function. Under these conditions, altered P53 stability and activity result in reduced cell death and increased cell senescence. This newly discovered function of Tau involves abnormal modification of P53 and its E3 ubiquitin ligase MDM2. Considering the medical need with vast social implications caused by neurodegeneration and cancer, our study may reform our approach to disease-modifying therapies.

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Autophagy Roles in Genome Maintenance

Cancers ◽

10.3390/cancers12071793 ◽

2020 ◽

Vol 12 (7) ◽

pp. 1793 ◽

Cited By ~ 3

Author(s):

Susanna Ambrosio ◽

Barbara Majello

Keyword(s):

Dna Damage ◽

Cell Fate ◽

Dna Damage Response ◽

Current Knowledge ◽

Response To Therapy ◽

Genome Integrity ◽

Genome Maintenance ◽

Damage Response ◽

Cancer Cell Survival ◽

Fate Decision

In recent years, a considerable correlation has emerged between autophagy and genome integrity. A range of mechanisms appear to be involved where autophagy participates in preventing genomic instability, as well as in DNA damage response and cell fate decision. These initial findings have attracted particular attention in the context of malignancy; however, the crosstalk between autophagy and DNA damage response is just beginning to be explored and key questions remain that need to be addressed, to move this area of research forward and illuminate the overall consequence of targeting this process in human therapies. Here we present current knowledge on the complex crosstalk between autophagy and genome integrity and discuss its implications for cancer cell survival and response to therapy.

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Mathematical model identifies effective P53 accumulation with target gene binding affinity in DNA damage response for cell fate decision

Cell Cycle ◽

10.1080/15384101.2018.1553342 ◽

2018 ◽

Vol 17 (24) ◽

pp. 2716-2730 ◽

Cited By ~ 2

Author(s):

Tingzhe Sun ◽

Dan Mu ◽

Jun Cui

Keyword(s):

Mathematical Model ◽

Dna Damage ◽

Cell Fate ◽

Binding Affinity ◽

Dna Damage Response ◽

Target Gene ◽

Cell Fate Decision ◽

Damage Response ◽

Fate Decision

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Faculty Opinions recommendation of Senataxin, defective in the neurodegenerative disorder ataxia with oculomotor apraxia 2, lies at the interface of transcription and the DNA damage response.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.717967738.793476866 ◽

2013 ◽

Author(s):

R Scott Williams ◽

Bret Wallace

Keyword(s):

Dna Damage ◽

Dna Damage Response ◽

Neurodegenerative Disorder ◽

Oculomotor Apraxia ◽

Damage Response ◽

Ataxia With Oculomotor Apraxia

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Profilin-1; a novel regulator of DNA damage response and repair machinery in keratinocytes

Molecular Biology Reports ◽

10.1007/s11033-021-06210-6 ◽

2021 ◽

Author(s):

Chang-Jin Lee ◽

Min-Ji Yoon ◽

Dong Hyun Kim ◽

Tae Uk Kim ◽

Youn-Jung Kang

Keyword(s):

Dna Damage ◽

Dna Repair ◽

Dna Damage Response ◽

Recovery Time ◽

Actin Polymerization ◽

Loss Of Function ◽

Dna Double Strand Breaks ◽

Pten Loss ◽

Damage Response ◽

Specific Regulation

AbstractProfilin-1 (PFN1) regulates actin polymerization and cytoskeletal growth. Despite the essential roles of PFN1 in cell integration, its subcellular function in keratinocyte has not been elucidated yet. Here we characterize the specific regulation of PFN1 in DNA damage response and repair machinery. PFN1 depletion accelerated DNA damage-mediated apoptosis exhibiting PTEN loss of function instigated by increased phosphorylated inactivation followed by high levels of AKT activation. PFN1 changed its predominant cytoplasmic localization to the nucleus upon DNA damage and subsequently restored the cytoplasmic compartment during the recovery time. Even though γH2AX was recruited at the sites of DNA double strand breaks in response to DNA damage, PFN1-deficient cells failed to recruit DNA repair factors, whereas control cells exhibited significant increases of these genes. Additionally, PFN1 depletion resulted in disruption of PTEN-AKT cascade upon DNA damage and CHK1-mediated cell cycle arrest was not recovered even after the recovery time exhibiting γH2AX accumulation. This might suggest PFN1 roles in regulating DNA damage response and repair machinery to protect cells from DNA damage. Future studies addressing the crosstalk and regulation of PTEN-related DNA damage sensing and repair pathway choice by PFN1 may further aid to identify new mechanistic insights for various DNA repair disorders.

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DNA Damage and DNA Damage Response in Chronic Myeloid Leukemia

International Journal of Molecular Sciences ◽

10.3390/ijms21041177 ◽

2020 ◽

Vol 21 (4) ◽

pp. 1177 ◽

Cited By ~ 2

Author(s):

Popp ◽

Kohl ◽

Naumann ◽

Flach ◽

Brendel ◽

...

Keyword(s):

Dna Damage ◽

Chronic Myeloid Leukemia ◽

Dna Damage Response ◽

Myeloid Leukemia ◽

Molecular Response ◽

Blastic Transformation ◽

Γh2ax Foci ◽

Damage Response ◽

Nhej Repair ◽

Repair Mechanisms

DNA damage and alterations in the DNA damage response (DDR) are critical sources of genetic instability that might be involved in BCR-ABL1 kinase-mediated blastic transformation of chronic myeloid leukemia (CML). Here, increased DNA damage is detected by γH2AX foci analysis in peripheral blood mononuclear cells (PBMCs) of de novo untreated chronic phase (CP)-CML patients (n = 5; 2.5 γH2AX foci per PBMC ± 0.5) and blast phase (BP)-CML patients (n = 3; 4.4 γH2AX foci per PBMC ± 0.7) as well as CP-CML patients with loss of major molecular response (MMR) (n = 5; 1.8 γH2AX foci per PBMC ± 0.4) when compared to DNA damage in PBMC of healthy donors (n = 8; 1.0 γH2AX foci per PBMC ± 0.1) and CP-CML patients in deep molecular response or MMR (n = 26; 1.0 γH2AX foci per PBMC ± 0.1). Progressive activation of erroneous non-homologous end joining (NHEJ) repair mechanisms during blastic transformation in CML is indicated by abundant co-localization of γH2AX/53BP1 foci, while a decline of the DDR is suggested by defective expression of (p-)ATM and (p-)CHK2. In summary, our data provide evidence for the accumulation of DNA damage in the course of CML and suggest ongoing DNA damage, erroneous NHEJ repair mechanisms, and alterations in the DDR as critical mediators of blastic transformation in CML.

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Role of GOLPH3 and TPX2 in Neuroblastoma DNA Damage Response and Cell Resistance to Chemotherapy

International Journal of Molecular Sciences ◽

10.3390/ijms20194764 ◽

2019 ◽

Vol 20 (19) ◽

pp. 4764 ◽

Cited By ~ 6

Author(s):

Marzia Ognibene ◽

Marina Podestà ◽

Alberto Garaventa ◽

Annalisa Pezzolo

Keyword(s):

Dna Damage ◽

Dna Damage Response ◽

Mammalian Cells ◽

Neuroblastoma Cell ◽

Neuroblastoma Cells ◽

Preschool Age ◽

Human Neuroblastoma Cell ◽

Human Neuroblastoma ◽

Therapeutic Benefits ◽

Damage Response

Neuroblastoma (NB) is an aggressive, relapse-prone infancy tumor of the sympathetic nervous system and is the leading cause of death among preschool age diseases, so the search for novel therapeutic targets is crucial. Golgi phosphoprotein 3 (GOLPH3) has been reported to be involved in the development, and in the DNA damage response, of various human cancers. Golgi dispersal is a common feature of DNA damage response in mammalian cells. Understanding how cells react to DNA damage is essential in order to recognize the systems used to escape from elimination. We induced DNA damage in two human neuroblastoma cell lines by curcumin. The exposure of neuroblastoma cells to curcumin induced: (a) up-regulation of GOLPH3+ cells; (b) augmentation of double-strand breaks; (c) Golgi fragmentation and dispersal throughout the cytoplasm; (d) increase of apoptosis and autophagy; (e) increased expression of TPX2 oncoprotein, able to repair DNA damage. Primary neuroblastoma samples analysis confirmed these observations. Our findings suggest that GOLPH3 expression levels may represent a clinical marker of neuroblastoma patients’ responsiveness to DNA damaging therapies—and of possible resistance to them. Novel molecules able to interfere with GOLPH3 and TPX2 pathways may have therapeutic benefits when used in combination with standard DNA damaging therapeutic agents in neuroblastoma

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Coordination between Cell Cycle Progression and Cell Fate Decision by the p53 and E2F1 Pathways in Response to DNA Damage

Journal of Biological Chemistry ◽

10.1074/jbc.m110.134650 ◽

2010 ◽

Vol 285 (41) ◽

pp. 31571-31580 ◽

Cited By ~ 36

Author(s):

Xiao-Peng Zhang ◽

Feng Liu ◽

Wei Wang

Keyword(s):

Cell Cycle ◽

Dna Damage ◽

Cell Fate ◽

Cell Cycle Progression ◽

Cell Fate Decision ◽

Cycle Progression ◽

Fate Decision

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Cellular responses to a prolonged delay in mitosis are determined by a DNA damage response controlled by Bcl-2 family proteins

Open Biology ◽

10.1098/rsob.140156 ◽

2015 ◽

Vol 5 (3) ◽

pp. 140156 ◽

Cited By ~ 32

Author(s):

Didier J. Colin ◽

Karolina O. Hain ◽

Lindsey A. Allan ◽

Paul R. Clarke

Keyword(s):

Cell Cycle ◽

Dna Damage ◽

Protein Kinases ◽

Cell Fate ◽

Dna Damage Response ◽

Cell Cycle Progression ◽

Cycle Progression ◽

Anti Cancer ◽

Damage Response ◽

Microtubule Poisons

Anti-cancer drugs that disrupt mitosis inhibit cell proliferation and induce apoptosis, although the mechanisms of these responses are poorly understood. Here, we characterize a mitotic stress response that determines cell fate in response to microtubule poisons. We show that mitotic arrest induced by these drugs produces a temporally controlled DNA damage response (DDR) characterized by the caspase-dependent formation of γH2AX foci in non-apoptotic cells. Following exit from a delayed mitosis, this initial response results in activation of DDR protein kinases, phosphorylation of the tumour suppressor p53 and a delay in subsequent cell cycle progression. We show that this response is controlled by Mcl-1, a regulator of caspase activation that becomes degraded during mitotic arrest. Chemical inhibition of Mcl-1 and the related proteins Bcl-2 and Bcl-x L by a BH3 mimetic enhances the mitotic DDR, promotes p53 activation and inhibits subsequent cell cycle progression. We also show that inhibitors of DDR protein kinases as well as BH3 mimetics promote apoptosis synergistically with taxol (paclitaxel) in a variety of cancer cell lines. Our work demonstrates the role of mitotic DNA damage responses in determining cell fate in response to microtubule poisons and BH3 mimetics, providing a rationale for anti-cancer combination chemotherapies.

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