DNA damage response of haematopoietic stem and progenitor cells to high-LET neutron irradiation

Engelbrecht, Monique; Ndimba, Roya; Kock, Maryna de; Miles, Xanthene; Nair, Shankari; Fisher, Randall; Plessis, Peter du; Bolcaen, Julie; Botha, Matthys H.; Zwanepoel, Elbie; Sioen, Simon; Baeyens, Ans; Nieto-Camero, Jaime; Kock, Evan de; Vandevoorde, Charlot

doi:10.1038/s41598-021-00229-2

Cited by 5 publications

(6 citation statements)

References 68 publications

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“…Flow cytometry analysis of Annexin V- and 7-amino-actinomycin-positive cells exposed to different doses of γ-rays or boron ions reveals a three-fold increase in apoptosis 48 h after exposure to high-LET ions as compared to low-LET IR [ 50 ]. Another report came to similar conclusions [ 65 ] and demonstrated increased levels of late apoptosis in hematopoietic and progenitor cells exposed to low doses of neutrons. Neutron irradiation also increases the rates of early apoptosis in osteosarcoma cells, as compared to γ-rays and is associated with enhanced Caspase-3 and Caspase-9 expression and cleavage, PARP-1 cleavage and increased reactive oxygen species production [ 66 ].…”

Section: Exposure To High-let Ir Activates Signaling Network Mainly R...supporting

confidence: 63%

DNA Damage Clustering after Ionizing Radiation and Consequences in the Processing of Chromatin Breaks

et al. 2022

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Charged-particle radiotherapy (CPRT) utilizing low and high linear energy transfer (low-/high-LET) ionizing radiation (IR) is a promising cancer treatment modality having unique physical energy deposition properties. CPRT enables focused delivery of a desired dose to the tumor, thus achieving a better tumor control and reduced normal tissue toxicity. It increases the overall radiation tolerance and the chances of survival for the patient. Further improvements in CPRT are expected from a better understanding of the mechanisms governing the biological effects of IR and their dependence on LET. There is increasing evidence that high-LET IR induces more complex and even clustered DNA double-strand breaks (DSBs) that are extremely consequential to cellular homeostasis, and which represent a considerable threat to genomic integrity. However, from the perspective of cancer management, the same DSB characteristics underpin the expected therapeutic benefit and are central to the rationale guiding current efforts for increased implementation of heavy ions (HI) in radiotherapy. Here, we review the specific cellular DNA damage responses (DDR) elicited by high-LET IR and compare them to those of low-LET IR. We emphasize differences in the forms of DSBs induced and their impact on DDR. Moreover, we analyze how the distinct initial forms of DSBs modulate the interplay between DSB repair pathways through the activation of DNA end resection. We postulate that at complex DSBs and DSB clusters, increased DNA end resection orchestrates an increased engagement of resection-dependent repair pathways. Furthermore, we summarize evidence that after exposure to high-LET IR, error-prone processes outcompete high fidelity homologous recombination (HR) through mechanisms that remain to be elucidated. Finally, we review the high-LET dependence of specific DDR-related post-translational modifications and the induction of apoptosis in cancer cells. We believe that in-depth characterization of the biological effects that are specific to high-LET IR will help to establish predictive and prognostic signatures for use in future individualized therapeutic strategies, and will enhance the prospects for the development of effective countermeasures for improved radiation protection during space travel.

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Section: Exposure To High-let Ir Activates Signaling Network Mainly R...supporting

confidence: 63%

DNA Damage Clustering after Ionizing Radiation and Consequences in the Processing of Chromatin Breaks

et al. 2022

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“…Then, HSPCs were purified by using CD34 + immunomagnetic beads (human CD34 + Microbead kit, Miltenyi Biotec Inc., Bergisch Gladbach, Germany) according to the manufacturer’s guidelines. CD34+ purity and viability were checked as previously described by Engelbrecht et al 35 . Flow cytometric analysis revealed an average CD34 + purity of 95.47% (SD: 3.62%) and a viability minimum was set at 95%.…”

Section: Methodsmentioning

confidence: 99%

“…After irradiation, cells of one vial were seeded out in two wells of a 48-well suspension plate (Greiner Cellstar ® , Sigma-Aldrich). The cells were stimulated into division and the CD34 + micro-culture CBMN assay was performed as recently described by Engelbrecht et al 35 . The nuclear division index (NDI) provides a measure of the cell’s proliferative status.…”

Section: Methodsmentioning

confidence: 99%

“…Multiple studies have suggested differences in DNA repair, cell survival and cell cycle perturbations between proton or photon therapy in different cells 33 , 34 . More specifically for human HSPCs, several studies on DNA damage response have been published with other radiation types but not with protons 35 – 37 . In this study, we investigated the differences in DNA damage induction and repair of human CD34 + cells, isolated out of umbilical cord blood (UCB), after exposure to high energy photon and proton irradiation at different SOBP positions by means of the γ-H2AX foci assay and the cytogenetic cytokinesis-block micronucleus assay (Supplementary file 1 ).…”

Section: Introductionmentioning

confidence: 99%

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Impact of proton therapy on the DNA damage induction and repair in hematopoietic stem and progenitor cells

Sioen,

Vanhove,

Vanderstraeten

et al. 2023

Sci Rep

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Proton therapy is of great interest to pediatric cancer patients because of its optimal depth dose distribution. In view of healthy tissue damage and the increased risk of secondary cancers, we investigated DNA damage induction and repair of radiosensitive hematopoietic stem and progenitor cells (HSPCs) exposed to therapeutic proton and photon irradiation due to their role in radiation-induced leukemia. Human CD34+ HSPCs were exposed to 6 MV X-rays, mid- and distal spread-out Bragg peak (SOBP) protons at doses ranging from 0.5 to 2 Gy. Persistent chromosomal damage was assessed with the micronucleus assay, while DNA damage induction and repair were analyzed with the γ-H2AX foci assay. No differences were found in induction and disappearance of γ-H2AX foci between 6 MV X-rays, mid- and distal SOBP protons at 1 Gy. A significantly higher number of micronuclei was found for distal SOBP protons compared to 6 MV X-rays and mid- SOBP protons at 0.5 and 1 Gy, while no significant differences in micronuclei were found at 2 Gy. In HSPCs, mid-SOBP protons are as damaging as conventional X-rays. Distal SOBP protons showed a higher number of micronuclei in HSPCs depending on the radiation dose, indicating possible changes of the in vivo biological response.

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“…Genomic instability results in a high frequency of mutation, including chromosomal rearrangements, aneuploidy and changes in nucleic acid sequences [5]. An increase in DNA damage caused by processes such as irradiation or a decrease in DNA repair activity promotes genomic instability [6]. Many studies have also indicated that various therapeutic methods, such as radiotherapy, chemotherapy, and targeted therapy, induce genomic instability, subsequently increasing tumor heterogeneity and ultimately leading to recurrence [7].…”

Section: Introductionmentioning

confidence: 99%

Tp53 haploinsufficiency is involved in hotspot mutations and cytoskeletal remodeling in gefitinib-induced drug-resistant EGFRL858R-lung cancer mice

et al. 2023

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Tumor heterogeneity is the major factor for inducing drug resistance. p53 is the major defender to maintain genomic stability, which is a high proportion mutated in most of the cancer types. In this study, we established in vivo animal models of gefitinib-induced drug-resistant lung cancer containing EGFRL858R and EGFRL858R*Tp53+/− mice to explore the molecular mechanisms of drug resistance by studying the genomic integrity and global gene expression. The cellular morphology of the lung tumors between gefitinib-induced drug-resistant mice and drug-sensitive mice were very different. In addition, in drug-resistant mice, the expression of many cytoskeleton-related genes were changed, accompanied by decreased amounts of actin filaments and increased amounts of microtubule, indicating that significant cytoskeletal remodeling is induced in gefitinib-induced drug-resistant EGFRL858R and EGFRL858R*Tp53+/− lung cancer mice. The gene expression profiles and involved pathways were different in gefitinib-sensitive, gefitinib-resistant and Tp53+/−-mice. Increases in drug resistance and nuclear size (N/C ratio) were found in EGFRL858R*Tp53+/− drug-resistant mice. Mutational hotspot regions for drug resistance via Tp53+/+- and Tp53+/−-mediated pathways are located on chromosome 1 and chromosome 11, respectively, and are related to prognosis of lung cancer cohorts. This study not only builds up a gefitinib-induced drug-resistant EGFRL858R lung cancer animal model, but also provides a novel mutation profile in a Tp53+/+- or Tp53+/−-mediated manner and induced cytoskeleton remodeling during drug resistance, which could contribute to the prevention of drug resistance during cancer therapy.

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DNA damage response of haematopoietic stem and progenitor cells to high-LET neutron irradiation

Cited by 5 publications

References 68 publications

DNA Damage Clustering after Ionizing Radiation and Consequences in the Processing of Chromatin Breaks

DNA Damage Clustering after Ionizing Radiation and Consequences in the Processing of Chromatin Breaks

Impact of proton therapy on the DNA damage induction and repair in hematopoietic stem and progenitor cells

Tp53 haploinsufficiency is involved in hotspot mutations and cytoskeletal remodeling in gefitinib-induced drug-resistant EGFRL858R-lung cancer mice

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