scholarly journals Strong Shift to ATR-Dependent Regulation of the G2-Checkpoint after Exposure to High-LET Radiation

Life ◽  
2021 ◽  
Vol 11 (6) ◽  
pp. 560
Author(s):  
Veronika Mladenova ◽  
Emil Mladenov ◽  
Michael Scholz ◽  
Martin Stuschke ◽  
George Iliakis
Keyword(s):  
Chromosomal Abnormalities ◽  
Biological Effects ◽  
Cell Killing ◽  
Space Environment ◽  
Low Doses ◽  
X Rays ◽  
G2 Checkpoint ◽  
High Let Radiation ◽  
High Let ◽  
Α Particles

The utilization of high linear-energy-transfer (LET) ionizing radiation (IR) modalities is rapidly growing worldwide, causing excitement but also raising concerns, because our understanding of their biological effects is incomplete. Charged particles such as protons and heavy ions have increasing potential in cancer therapy, due to their advantageous physical properties over X-rays (photons), but are also present in the space environment, adding to the health risks of space missions. Therapy improvements and the protection of humans during space travel will benefit from a better understanding of the mechanisms underpinning the biological effects of high-LET IR. There is evidence that high-LET IR induces DNA double-strand breaks (DSBs) of increasing complexity, causing enhanced cell killing, owing, at least partly, to the frequent engagement of a low-fidelity DSB-repair pathway: alternative end-joining (alt-EJ), which is known to frequently induce severe structural chromosomal abnormalities (SCAs). Here, we evaluate the radiosensitivity of A549 lung adenocarcinoma cells to X-rays, α-particles and 56Fe ions, as well as of HCT116 colorectal cancer cells to X-rays and α-particles. We observe the expected increase in cell killing following high-LET irradiation that correlates with the increased formation of SCAs as detected by mFISH. Furthermore, we report that cells exposed to low doses of α-particles and 56Fe ions show an enhanced G2-checkpoint response which is mainly regulated by ATR, rather than the coordinated ATM/ATR-dependent regulation observed after exposure to low doses of X-rays. These observations advance our understanding of the mechanisms underpinning high-LET IR effects, and suggest the potential utility for ATR inhibitors in high-LET radiation therapy.

Alpha-Particle Exposure Induces Mainly Unstable Complex Chromosome Aberrations which do not Contribute to Radiation-Associated Cytogenetic Risk

2021 ◽  
Author(s):  
C. Hartel ◽  
E. Nasonova ◽  
S. Ritter ◽  
T. Friedrich
Keyword(s):  
Ex Vivo ◽  
Human Peripheral Blood ◽  
Mitotic Cell ◽  
Peripheral Blood Lymphocytes ◽  
Small Scale ◽  
X Rays ◽  
Carcinogenic Effect ◽  
High Let Radiation ◽  
High Let ◽  
Α Particles

The mechanism underlying the carcinogenic potential of α radiation is not fully understood, considering that cell inactivation (e.g., mitotic cell death) as a main consequence of exposure efficiently counteracts the spreading of heritable DNA damage. The aim of this study is to improve our understanding of the effectiveness of α particles in inducing different types of chromosomal aberrations, to determine the respective values of the relative biological effectiveness (RBE) and to interpret the results with respect to exposure risk. Human peripheral blood lymphocytes (PBLs) from a single donor were exposed ex vivo to doses of 0–6 Gy X rays or 0–2 Gy α particles. Cells were harvested at two different times after irradiation to account for the mitotic delay of heavily damaged cells, which is known to occur after exposure to high-LET radiation (including α particles). Analysis of the kinetics of cells reaching first or second (and higher) mitosis after irradiation and aberration data obtained by the multiplex fluorescence in situ hybridization (mFISH) technique are used to determine of the cytogenetic risk, i.e., the probability for transmissible aberrations in surviving lymphocytes. The analysis shows that the cytogenetic risk after α exposure is lower than after X rays. This indicates that the actually observed higher carcinogenic effect of α radiation is likely to stem from small scale mutations that are induced effectively by high-LET radiation but cannot be resolved by mFISH analysis.

scholarly journals USP9X Is Required to Maintain Cell Survival in Response to High-LET Radiation

2021 ◽  
Vol 11 ◽  
Author(s):  
Catherine M. Nickson ◽  
Maria Rita Fabbrizi ◽  
Rachel J. Carter ◽  
Jonathan R. Hughes ◽  
Andrzej Kacperek ◽  
...  
Keyword(s):  
Dna Damage ◽  
Cell Survival ◽  
Cell Biology ◽  
Cellular Response ◽  
Biological Effects ◽  
Control Cell ◽  
X Rays ◽  
High Let Radiation ◽  
High Let ◽  
The Impact

Ionizing radiation (IR) principally acts through induction of DNA damage that promotes cell death, although the biological effects of IR are more broad ranging. In fact, the impact of IR of higher-linear energy transfer (LET) on cell biology is generally not well understood. Critically, therefore, the cellular enzymes and mechanisms responsible for enhancing cell survival following high-LET IR are unclear. To this effect, we have recently performed siRNA screening to identify deubiquitylating enzymes that control cell survival specifically in response to high-LET α-particles and protons, in comparison to low-LET X-rays and protons. From this screening, we have now thoroughly validated that depletion of the ubiquitin-specific protease 9X (USP9X) in HeLa and oropharyngeal squamous cell carcinoma (UMSCC74A) cells using small interfering RNA (siRNA), leads to significantly decreased survival of cells after high-LET radiation. We consequently investigated the mechanism through which this occurs, and demonstrate that an absence of USP9X has no impact on DNA damage repair post-irradiation nor on apoptosis, autophagy, or senescence. We discovered that USP9X is required to stabilize key proteins (CEP55 and CEP131) involved in centrosome and cilia formation and plays an important role in controlling pericentrin-rich foci, particularly in response to high-LET protons. This was also confirmed directly by demonstrating that depletion of CEP55/CEP131 led to both enhanced radiosensitivity of cells to high-LET protons and amplification of pericentrin-rich foci. Our evidence supports the importance of USP9X in maintaining centrosome function and biogenesis and which is crucial particularly in the cellular response to high-LET radiation.

scholarly journals Characterisation of deubiquitylating enzymes in the cellular response to high-LET ionising radiation and complex DNA damage

2018 ◽  
Author(s):  
Rachel J. Carter ◽  
Catherine M. Nickson ◽  
James M. Thompson ◽  
Andrzej Kacperek ◽  
Mark A. Hill ◽  
...  
Keyword(s):  
Dna Damage ◽  
Cell Survival ◽  
Cellular Response ◽  
Cell Killing ◽  
Dna Lesions ◽  
Ionising Radiation ◽  
X Rays ◽  
High Let Radiation ◽  
High Let ◽  
Parp 1

AbstractPurposeIonising radiation, particular high linear energy transfer (LET) radiation, can induce complex DNA damage (CDD) where two or more DNA lesions are induced in close proximity which contributes significantly to the cell killing effects. However knowledge of the enzymes and mechanisms involved in co-ordinating the recognition and processing of CDD in cellular DNA are currently lacking.Methods and MaterialsAn siRNA screen of deubiquitylation enzymes was conducted in HeLa cells irradiated with high-LET -particles or protons, versus low-LET protons and x-rays, and cell survival monitored by clonogenic assays. Candidates whose depletion led to decreased cell survival specifically in response to high-LET radiation were validated in both HeLa and oropharyngeal squamous cell carcinoma (UMSCC74A) cells, and the association with CDD repair was confirmed by using an enzyme modified neutral comet assay.ResultsDepletion of USP6 decreased cell survival specifically following high-LET α-particles and protons, but not by low-LET protons or x-rays. USP6 depletion caused cell cycle arrest and a deficiency in CDD repair mediated through instability of poly(ADP-ribose) polymerase-1 (PARP-1). This phenotype was mimicked using the PARP inhibitor olaparib.ConclusionUSP6 controls cell survival in response to high-LET radiation by stabilising PARP-1 protein levels which is essential for CDD repair. We also describe synergy between CDD induced by high-LET protons and PARP inhibition in effective cancer cell killing.

scholarly journals Immunomodulatory Effects of Radiotherapy

2020 ◽  
Vol 21 (21) ◽  
pp. 8151
Author(s):  
Sharda Kumari ◽  
Shibani Mukherjee ◽  
Debapriya Sinha ◽  
Salim Abdisalaam ◽  
Sunil Krishnan ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Carbon Particle ◽  
Dna Lesions ◽  
X Rays ◽  
Adaptive Immune ◽  
High Let Radiation ◽  
Different Types ◽  
High Let ◽  
Radiation Induced ◽  
Tumor Death

Radiation therapy (RT), an integral component of curative treatment for many malignancies, can be administered via an increasing array of techniques. In this review, we summarize the properties and application of different types of RT, specifically, conventional therapy with x-rays, stereotactic body RT, and proton and carbon particle therapies. We highlight how low-linear energy transfer (LET) radiation induces simple DNA lesions that are efficiently repaired by cells, whereas high-LET radiation causes complex DNA lesions that are difficult to repair and that ultimately enhance cancer cell killing. Additionally, we discuss the immunogenicity of radiation-induced tumor death, elucidate the molecular mechanisms by which radiation mounts innate and adaptive immune responses and explore strategies by which we can increase the efficacy of these mechanisms. Understanding the mechanisms by which RT modulates immune signaling and the key players involved in modulating the RT-mediated immune response will help to improve therapeutic efficacy and to identify novel immunomodulatory drugs that will benefit cancer patients undergoing targeted RT.

Mutagenic adaptive response to high-LET radiation in human lymphoblastoid cells exposed to X-rays

2011 ◽  
Vol 706 (1-2) ◽  
pp. 46-52 ◽  
Author(s):  
Guillaume Varès ◽  
Bing Wang ◽  
Kaoru Tanaka ◽  
Ayana Kakimoto ◽  
Kyomi Eguchi-Kasai ◽  
...  
Keyword(s):  
Adaptive Response ◽  
X Rays ◽  
Lymphoblastoid Cells ◽  
High Let Radiation ◽  
High Let

Potential for Therapeutic Gain - 29 MeV Neutrons versus 6 MeV Neutrons

2015 ◽  
Vol 1084 ◽  
pp. 559-566
Author(s):  
Jacobus Slabbert ◽  
Anne Vral
Keyword(s):  
Radiation Therapy ◽  
Tumor Cell ◽  
Cell Types ◽  
Cancer Type ◽  
X Rays ◽  
High Let Radiation ◽  
Therapeutic Gain ◽  
High Let

When a cancer type proves to be radioresistant to treatment with X-rays, the use of neutrons may constitute therapeutic gain provided the cells are relatively sensitive to high-LET radiation. In this work studies with different tumor cell types are reported following exposure to either photons or different neutron energies used in clinical radiation therapy. Potential for therapeutic gain is clearly noted for neutrons with a mean energy of 6 MeV whilst that for 29 MeV neutrons is dependent on the cell types used in the study.

scholarly journals The effects of X-rays on mitosis in the spermatogonial divisions of Locusta migratoria L

1935 ◽  
Vol 119 (812) ◽  
pp. 61-84 ◽  
Keyword(s):  
Recent Work ◽  
Gene Mutation ◽  
Chromosomal Abnormalities ◽  
Biological Effects ◽  
Locusta Migratoria ◽  
Mutation Rates ◽  
X Rays ◽  
Tissue Cultures ◽  
Structural Alterations ◽  
Vertebrate Tissue

Although the fact that X-rays cause major structural alterations in chromosomes was actually known long before the discovery of their capacity for increasing gene mutation-rates our knowledge of the former type of effect has lagged behind. Nearly all the recent work on the biological effects of X-rays has been carried out on material such as vertebrate tissue-cultures which are extremely unfavourable for detailed study of chromosomes. Hence the very vague conceptions of the influence of radiation on the nucleus which are widespread in the literature; many authors referring to the sum total of these effects as the “sensitivity” of the nucleus to radiation. The literature dealing specifically with chromosomal abnormalities resulting from irradiation comprises only about nine papers (Helwig (1933); Huskins and Hunter (1935); Lewitsky and Araratian (1931); Mather and Stone (1934); Mather (1934); Navashin (1931); Stadler (1931); Stone (1933); and White (1935)). Of course, a great deal of work has been done on translocations and inversions produced by X-rays ( e. g. , Muller and Altenburg (1930): Muller, Prokofieva, and Raffel (1935)), but this only refers to cytologically and genetically viable abnormalities. It is obvious that these comprise only a small fraction of the total range of aberrations produced; the present paper, like those mentioned above, aims at recording all the artificially induced chromosome forms, whether capable of survival or not.

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