A Novel ATM/TP53/p21-Mediated Checkpoint Only Activated by Chronic γ-Irradiation

Cao, Lili; Kawai, Hidehiko; Sasatani, Megumi; Iizuka, Daisuke; Masuda, Yuji; Inaba, Toshiya; Suzuki, Keiji; Ootsuyama, Akira; Umata, Toshiyuki; Kamiya, Kenji; Suzuki, Fumio

doi:10.1371/journal.pone.0104279

Cited by 33 publications

(34 citation statements)

References 43 publications

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“…4A). Similar effects are observed in primary human fibroblasts cell lines during chronic exposure to IR [113]. Because lethal IR exposure irreversibly eliminates neoblasts, the results confirmed that key regulators of cell cycle progression and markers of proliferating neoblasts were nearly abolished upon IR (e.g.…”

Section: Evolutionarily Conserved Dna Damage Repair Mechanisms Exist supporting

confidence: 76%

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DNA damage and tissue repair: What we can learn from planaria

Barghouth

Thiruvalluvan

LeGro

et al. 2019

Seminars in Cell & Developmental Biology

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Faithful renewal of aging and damaged tissues is central to organismal lifespan. Stem cells (SCs) generate the cellular progeny that replenish adult tissues across the body but this task becomes increasingly compromised over time. The age related decline in SC-mediated tissue maintenance is a multifactorial event that commonly affects genome integrity. The presence of DNA damage in SCs that are under continuous demand to divide poses a great risk for age-related disorders such as cancer. However, performing analysis of SCs with genomic instability and the DNA damage response during tissue renewal present significant challenges. Here we introduce an alternative experimental system based on the planaria flatworm Schmidtea mediterranea to address at the organismal level studies intersecting SC-mediated tissue renewal in the presence of genomic instability. Planaria have abundant SCs (neoblasts) that maintain high rates of cellular turnover and a variety of molecular tools have been developed to induce DNA damage and dissect how neoblasts respond to this stressor. S. mediterranea displays high evolutionary conservation of DNA repair mechanisms and signaling pathways regulating adult SCs. We describe genetically induced-DNA damage models and highlight body-wide signals affecting cellular decisions such as survival, proliferation, and death in the presence of genomic instability. We also discuss transcriptomic changes in the DNA damage response during injury repair and propose DNA repair as key component of tissue regeneration. Additional studies using planaria will provide insights about mechanisms regulating survival and growth of cells with DNA damage during tissue renewal and regeneration.

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Section: Evolutionarily Conserved Dna Damage Repair Mechanisms Exist supporting

confidence: 76%

“…4C). ATM is an important player of the DDR that influences cellular decisions upon IR through reg- ulation of p53/p21 axis to facilitate cell cycle checkpoint arrest [113,118]. Thus, we can postulate that Smed-ATM may be key to facilitating an appropriate cellular response to DSBs (e.g.…”

Section: Evolutionarily Conserved Dna Damage Repair Mechanisms Exist mentioning

confidence: 99%

DNA damage and tissue repair: What we can learn from planaria

Barghouth

Thiruvalluvan

LeGro

et al. 2019

Seminars in Cell & Developmental Biology

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“…These features were primarily typical for the most affected group of IR-exposed patients, namely, cleanup workers engaged in action in the 2 nd quarter of 1986. These preliminary findings don't contradict the assumption on possible influence of IR on CLL development, and are in accordance with the data evidencing that cellular responses on IR are realized mainly through the p53-dependent pathway [28].…”

Section: Resultssupporting

confidence: 90%

The Distribution of Tp53 Gene Polymorphisms in Chronic Lymphocytic Leukemia Patients, Sufferers of Chornobyl Nuclear Power Plant Accident

et al. 2016

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Previous analyses in a cohort of Chornobyl cleanup workers revealed significantly increased radiation-related risk for all leukemia types, including chronic lymphocytic leukemia (CLL). Numerous investigations emphasized the significance of genetic susceptibility to the radiation carcinogenesis. The aim of the work was to study the distribution of TP53 single nucleotide polymorphisms (SNPs) in CLL patients exposed to ionizing radiation (IR) due to Chornobyl nuclear power plant accident and estimate their impact on disease development. Materials and Methods: The TP53 exonic and intronic SNPs were analyzed in 236 CLL patients by polymerase chain reaction and direct sequencing. The main group included 106 IR exposed CLL patients and the control group was composed of 130 IR non-exposed CLL patients. Results: Nineteen TP53 SNPs were found in the observed CLL cohort. No significant differences were found between the main and the control groups, but increased frequencies of T/T rs12947788 + G/G rs12951053 homozygotes and rs146340390 C/T variants were found among IR-exposed CLL patients compared with healthy Europeans (data from the 1000 Genomes Project). Rare nucleotide substitution rs146340390 (c.665C>T) was found only in the main group. These features were primarily typical for the most affected group of IR-exposed patients, namely, cleanup workers engaged in emergency works in the 2nd quarter of 1986. Conclusion: These preliminary findings don’t contradict the assumption on possible influence of IR on CLL development via the p53-dependent pathway. This article is a part of a Special Issue entitled “The Chornobyl Nuclear Accident: Thirty Years After”.

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“…5D, right model). By contrast, in normal cells with wild-type p53, the classical ATM-p53-p21 pathway is a dominant irradiation response pathway (25). The difference in our model was that the radiation dose was insufficient for stimulating overexpression and phosphorylation of p53.…”

Section: Discussionmentioning

confidence: 89%

Low-dose irradiation inhibits proliferation of the p53null type human prostate cancer cells through the ATM/p21 pathway

Liang

et al. 2017

Int J Mol Med

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Low-dose ionizing radiation (LDIR) induces hormesis, exerts an adoptive effect on normal mammalian cells and stimulates cell proliferation; however, this effect is absent in cancer cells. Little is known on the molecular mechanisms underlying this differential response between normal and cancer cells. In the present study, it was demonstrated that the human prostate cancer cell line PC-3 and the normal prostate cell line RWPE-1 exhibited differential biological responses to LDIR. Through cell cycle analyses, it was demonstrated that LDIR inhibited cell growth and arrested the cell cycle at the S and G2/M phases in PC-3 cells, but not in RWPE-1 cells. Using western blotting, it was demonstrated that LDIR at 75 mGy induced the expression of ataxia-telangiectasia mutated (ATM) protein in PC-3 as well as RWPE-1 cells. However, the ATM̸p21 pathway was activated in PC-3, but not in RWPE-1 cells. Although the expression of p53 was not affected by 75 mGy LDIR in RWPE-1 cells, the ATM̸p21 pathway was activated when RWPE-1 cells lost p53 function. In addition, when using ATM inhibitors, the ATM̸p21 pathway was inactivated in both cell lines, and the LDIR-induced cell proliferation inhibition was also abolished. These findings suggested that the ATM/p21 pathway directly participated in the LDIR-induced cell proliferation inhibition in p53null type prostate tumor cells, whereas this mechanism was absent in normal prostate cells. Thus, p53 may affect cell stability following LDIR, and plays a crucial role in regulating the ATM/p21 pathway activated by LDIR.

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A Novel ATM/TP53/p21-Mediated Checkpoint Only Activated by Chronic γ-Irradiation

Cited by 33 publications

References 43 publications

DNA damage and tissue repair: What we can learn from planaria

DNA damage and tissue repair: What we can learn from planaria

The Distribution of Tp53 Gene Polymorphisms in Chronic Lymphocytic Leukemia Patients, Sufferers of Chornobyl Nuclear Power Plant Accident

Low-dose irradiation inhibits proliferation of the p53null type human prostate cancer cells through the ATM/p21 pathway

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