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Upregulation of DNA repair genes and cell extrusion underpin the remarkable radiation resistance of Trichoplax adhaerens

['Angelo Fortunato', 'Arizona Cancer Evolution Center', 'Arizona State University', 'Tempe', 'Arizona', 'United States Of America', 'Biodesign Center For Biocomputing', 'Security', 'Society', 'School Of Life Sciences']

Date: 2021-11

Trichoplax adhaerens is the simplest multicellular animal with tissue differentiation and somatic cell turnover. Like all other multicellular organisms, it should be vulnerable to cancer, yet there have been no reports of cancer in T. adhaerens or any other placozoan. We investigated the cancer resistance of T. adhaerens, discovering that they are able to tolerate high levels of radiation damage (218.6 Gy). To investigate how T. adhaerens survive levels of radiation that are lethal to other animals, we examined gene expression after the X-ray exposure, finding overexpression of genes involved in DNA repair and apoptosis including the MDM2 gene. We also discovered that T. adhaerens extrudes clusters of inviable cells after X-ray exposure. T. adhaerens is a valuable model organism for studying the molecular, genetic, and tissue-level mechanisms underlying cancer suppression.

Funding: This work was supported in part by the Arizona Cancer and Evolution Center, National Institutes of Health U54 CA217376 (C.C.M), Extension to the HTAN Pre-Cancer Atlas Project, National Institutes of Health U2C CA233254 (C.C.M), Biostatistics and Evolutionary Analysis, National Institutes of Health P01 CA91955 (C.C.M), Application of Evolutionary Principles to Maintain Cancer Control, National Institutes of Health R01 CA170595 (C.C.M), Genomic Diversity and Microenvironment as Drivers of Metastasis in DCIS, National Institutes of Health R01 CA185138 (C.C.M), Modeling Neoplastic Progression in Barrett's Esophagus, National Institutes of Health, R01 CA140657 (C.C.M), Genomic Diversity and the Microenvironment as Drivers of Progression in DCIS, Department of Defense, Congressionally Directed Medical Research BC132057 (C.C.M), The Arizona Biomedical Research Commission ADHS18-198847 (C.C.M) and Arizona Cancer and Evolution pilot grant (A.F.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Copyright: © 2021 Fortunato et al. This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

It is an open question whether the lack of reports of cancer in T. adhaerens is due to a lack of studies or the ability of the animal to resist cancer. We set out to answer this question through exposing T. adhaerens to radiation and observing changes in their phenotypes and gene expression. By studying cancer resistance in T. adhaerens, it is possible to gain a window into the biological processes and the molecular mechanisms of cancer suppression that likely evolved in the earliest animals.

Other invertebrates, such as Caenorhabditis elegans and Drosophila melanogaster, have been useful in molecular biology and the basic sciences [ 17 , 18 ]. However, they are not ideal models for cancer research because they do not have sustained somatic cell turnover and so do not risk the mutations due to errors in DNA synthesis. In addition, their life spans are very short, precluding the opportunity to develop cancer. T. adhaerens, on the other hand, have somatic cell turnover and very long life spans—a single organism can reproduce asexually in the lab for decades [ 19 ]. Even with these factors that would typically predispose organisms to cancer—cell turnover and long life span—there have been no reports of cancer in T. adhaerens, despite these organisms having been studied in the laboratory since 1969 [ 12 ]. In addition, the genome of T. adhaerens has been sequenced [ 20 ], which enables us to analyze the evolution of cancer genes, detect somatic mutations, and quantify gene expression. Despite T. adhaerens’ being evolutionarily ancient, most of the known cancer genes in humans have homologs in T. adhaerens [ 20 ].

(A) Untreated specimens of T. adhaerens, the animal on the right is folding. (B) Magnification of a single untreated T. adhaerens. (C) Sections of the animals can become elongated (arrows), 20 days after 218.6 Gy exposure. (D) Dark tissue mass (asterisk) in the middle of what is either a small animal or extrusion, 70 days after 143.6 Gy exposure. (E) Dark tissue mass projecting from the dorsal epithelium (arrow) of a T. adhaerens, 82 days after 143.6 Gy exposure. (F) A folded T. adhaerens that is not moving, 36 days after 80 Gy exposure; this animal eventually recovered.

We used Trichoplax adhaerens (Placozoa) as our model organism for the present study. T. adhaerens is the simplest multicellular animal organism ever described ( Fig 1A and 1B ). They are also ancient evolutionarily speaking, having diverged from other animals approximately 800 million years ago [ 9 ]. T. adhaerens is a disk-shaped, free-living marine organism, 2 to 3 mm wide and approximately 15 μm high. It is composed of only 5 somatic cell types, organized into 3 layers. T. adhaerens lack nervous and muscle tissues as well as a digestive system and specialized immune cells. They glide using the cilia of the lower epithelial layer. T. adhaerens feed on diatom algae by external digestion. In the laboratory, they reproduce only asexually through fission or budding [ 10 – 13 ], and they feed cooperatively [ 14 ]. It is possible to experimentally induce sexual reproduction in the lab, but the embryos do not complete development [ 10 ]. It is unknown if T. adhaerens reproduce sexually in the wild. T. adhaerens can detach from the plate surface when food is depleted and float on the water’s surface. T. adhaerens can be collected from the natural world by placing slides in the water column where they are presumably floating [ 15 , 16 ], suggesting that floating is part of the normal behavioral repertoire of T. adhaerens.

Theoretically, cancer is a disease that can affect all multicellular organisms, and cancer-like phenomena have been observed in all 7 branches of the tree of life that independently evolved complex multicellarity [ 1 ]. Generally speaking, somatic cells must limit their own proliferation in order for the organism to survive and effectively reproduce. Over the course of 2 billion years, multicellular organisms have evolved many mechanisms to suppress cancer, including control of cell proliferation. Complex multicellularity has evolved independently at least 7 times, and there is evidence of cancer-like phenomena on each of those 7 branches on the tree of life [ 1 ]. Although virtually every cell in a multicellular body has the potential to generate a cancer, and that risk accumulates over time, there is generally no association between body size or life span and cancer risk, an observation known as Peto’s Paradox [ 2 – 5 ]. This is likely because there has been selective pressure on large, long-lived organisms to evolve better mechanisms to prevent cancer than small, short-lived organisms [ 6 ]. This implies that nature has discovered a diversity of cancer suppression mechanisms, which we have only begun to explore for their applications to cancer prevention and treatment in humans [ 7 , 8 ].

We compared 50 random untreated control animals to 50 random animals exposed to X-rays after 2 years. We detected 3,637 total mutations (72.7 mutations per animal on average, of which 5 mutations were coding genes, excluding nonsynonymous mutations) in the X-ray-exposed animals but not in the controls. The number of mutations is strongly reduced compared to the number of mutations detected after 82 and 72 days from X-ray exposure ( Fig 4 ), suggesting that the animals can remove mutations over time. We found that mutated genes with ADP binding function were overrepresented (PANTHER overrepresentation test, fold enrichment = 18.14, FDR < 0.0001). All these genes (TRIADG62071, TRIADG62073, TRIADG62368, TRIADG62451, TRIADG62462, TRIADG62501, TRIADG62549, and TRIADG62630) coding for NB-ARC domain-containing protein (Apoptotic Protease-Activating Factor 1 family, PANTHER). We found 68 genes assigned to this family in T. adhaerens but only one in humans (APAF1), PATHER).

(A) Single base substitutions induced by X-ray exposure. (B) Short deletions (40.2%) are statistically more abundant than insertions (36.7%) (paired t test, P = 0.01). (C) Number of mutations in T. adhaerens X-ray-exposed parental and X-ray-exposed extrusion samples. Both types of samples have a high number of mutations. (D) Mutated coding genes overlap between X-ray-exposed parental and X-ray-exposed extrusion samples, after excluding synonymous mutations. The moderate overlap between X-ray-exposed parental and X-ray-exposed extrusion samples suggests a different mutational profile between X-ray-exposed parental and X-ray-exposed extrusion samples. The data used to generate this figure can be found in S6 Data . C1 and D1, organism 1; C2 and D2, organism 2; Small asym. fission, Small asymmetric fission.

We sequenced the genomes of 2 independent pairs of parental X-ray-exposed animals and their extruded bodies (as well as a viable, smaller T. adhaerens derived from an asymmetric fission of the first parental X-ray-exposed animal). We found an average of 1,847.8 mutations per Mb ( S2 Table ). In regions of the genome where both X-ray-exposed parental samples had at least 10X converge, 0.59% of the detected mutations were shared. Moreover, we found that only 11.9% ± 1.1 SD of the total variants detected in all the specimens and 1.9% ± 0.4 SD of the coding variants were present in the untreated control population (n = 50) of T. adhaerens, suggesting that most detected mutations were caused by the X-ray exposure ( Fig 4 and S6 Data ). These percentage values should be understood as maximum overlap between controls and X-ray-exposed specimens because not all variants present in the population are necessarily present in the same X-ray-exposed specimen. When we described the mutational signature of the treated samples, we found a statistically significant increase of the short deletions in all 5 samples compared to short insertions (paired t test, P = 0.01). This finding is compatible with the mutational profile induced by X-ray exposure ( Fig 4 and S6 Data ). There is a moderate overlap between mutated genes of parental and extrusion samples (Jaccard similarity index, group 1 = 0.05 (5%), group 2 = 0.04 (4%)), suggesting a different mutational profile between parental and extrusion samples. We did not find a statistically significant functional enrichment of mutations in the parental and extrusion samples.

We focused on 2 genes: TP53 (TriadG64021) and MDM2 (TriadG54791), the main negative regulator of TP53, whose functions in the processes of apoptosis and oncogenesis is well known. MDM2 and TP53 genes are well conserved in T. adhaerens [ 22 ]. RNA-seq analysis suggests that MDM2 is overexpressed (20-fold), while the expression of TP53 is similar to its expression in controls. Thus, we conducted additional experiments to investigate MDM2 and TP53 genes’ expression, exposing the animals to 218.6 Gy of X-rays. The RNA was extracted at different times after being exposed to X-rays (2, 6, 12, 24, and 48 hours). MDM2 and TP53 genes’ expression was analyzed by real-time PCR. We found that the expression of MDM2 was higher (12-fold) after 2 hours from the beginning of the experiment and decreased over time. On the other hand, the expression of TP53 was lower and indistinguishable from the controls across all time points (Mann–Whitney test, MDM2 versus control, P < 0.05; TP53 versus control, P = NS, S5 Fig and S5 Data ).

We extracted and sequenced RNA from 120 animals 2 hours after the maximal tolerable dose of X-rays (218.6 Gy). We focused on the overexpressed genes because X-ray exposure can generally reduce gene expression. We found 74 genes significantly overexpressed (logFC > 2, FDR < 0.05) after 2 hours from X-ray exposure ( Table 1 and S1 Table ). Among these, 5 genes with a human ortholog (given in parentheses) are involved in DNA double-strand break repair mechanisms: TriadG28563 (RAD52), TriadG50031 (LIG4), TriadG53902 (DCLRE1C), TriadG25695 (RECQL5), TriadG61626 (XRCC6). Other genes such as TriadG55661, TriadG51590, TriadG50243 (POLB), TriadG51591, TriadG28268 (POLL), and TriadG57566 (LIG3) are involved in different mechanisms of DNA repair. Interestingly, the TriadG28470 (EIF41B) radioresistant gene [ 21 ] is overexpressed after treatment. In addition, we identified up-regulated genes involved in signaling, microtubules activity, transporters, stress response, and other functions. There is marginal or no functional information for 20 of the overexpressed genes ( S1 Table ).

(A) Extrusion (arrows) of brownish putative cancer-like cells; insert, magnification of the same extrusion. (B) The cancer-like cells and the normal cells detached from the main body formed a new animal. The extrusion was observed and isolated 37 days after X-ray exposure. (C) Over time, the clear, apparently normal cells of the extruded body reduce in number, leaving only the apparently damaged cells, which eventually died. This specimen was exposed to 143.6 Gy X-rays. (A) Bright field, insert; (B and C) DIC, scale bars = 50 μm. DIC, differential interference contrast.

The extruded bodies ( Fig 3 ) initially are flat and attached to the plate’s bottom, but before dying, they acquire a spherical shape ( S2 Fig ). In order to estimate the number of extrusions per animal and to monitor the morphological changes over time, we transferred a single animal per well into 24-well plates seeded with algae of both control and experimental plates immediately after X-ray exposure. A week after X-ray exposure, the dead extruded buds (65 out of 83 buds) from the experimental animals exceeded the number of dead buds (5 out of 71 buds) in the control (Fisher exact test, P < 0.00001). In addition to regular buds, we observed extruded disk-shaped or spherical microbuds (n = 16, ⌀ = 182.01 μm ± 23.40 SEM) in the experimental plates, but not in the control plates. These microbuds are only visible at higher magnification, and we did not include them in the number and size measurements of organisms presented in Fig 2 .

T. adhaerens were counted and measured under the microscope, and the reported values are a combination of the organisms of all sizes including extrusions. (A) Number of T. adhaerens in control (green) and X-ray-exposed experimental plates (red) before (0 hour) exposure, and then 24, 48, 72 hours, and 7 days after exposure to 143.6 Gy of X-rays. Center line = median, box limits indicate the 25th and 75th percentiles. (B) Size of T. adhaerens in T. adhaerens in control (green) and X-ray-exposed experimental plates (red) before (0 hour), after 24, 48, and 72 hours 143.6 Gy of X-ray exposure. Histograms represent the mean ± SEM. (error bars). The data used to generate this figure can be found in S2 and S3 Data .

We found that the total number of discrete T. adhaerens entities (including both parents and extruded cells) rapidly increased through budding and fission immediately after X-ray irradiation (repeated measurement ANOVA, P < 0.01, Fig 2A and S2 and S3 Data) and their size significantly decreased (repeated measurement ANOVA, P < 0.0001, Fig 2B ), suggesting that the animals extrude cells or divided without physiological cell proliferation to regenerate their original size. After day 7, the total number of T. adhaerens in the treated group began to decrease ( Fig 2A ).

We exposed T. adhaerens to different levels of X-ray radiation and counted the number of individuals each day over 8 days after exposure. We then counted them every day for 8 days ( S1 Fig and S1 Data ). T. adhaerens can tolerate 218.6 Gy maximum single-dose X-ray exposure. No T. adhaerens survived exposure to 256.5 Gy of X-rays. At 218.6 Gy, less than 5% of the T. adhaerens survived (measuring the exact percentage is challenging because T. adhaerens divide and extrude cells during the experiment, but we calculated a lethality of 83.3% after 8 days). These surviving T. adhaerens were able to repopulate the culture after 30 days of exposure to 218.6 Gy. We found a statistically significant positive correlation between the doses of radiation (0, 143.6, 181.1, 218.6, 256.5, 294.5, and 332.5 Gy) and the number of T. adhaerens, Pearson correlation, r = 0.814, P = 0.026, calculated as the average of the first 4 days before the beginning of animal death caused by radiation. All the doses, with the exception of 143.6 Gy, cause a sharp decrease in the number of animals by 8 days after the exposure ( S1 Fig ). We observed morphological and behavioral changes after X-ray exposure, including blisters, changes in the shape of the animals, darker cellular aggregates, and extrusion of clusters of cells ( Fig 1C–1F ). These morphological changes were reversible in the animals that survived. T. adhaerens that survived also appeared to fully recover.

We found that T. adhaerens are able to tolerate high levels of radiation and are resilient to DNA damage. Exposure to X-rays triggered the extrusion of clusters of cells, which subsequently died. We also found that radiation exposure induced the overexpression of genes involved in DNA repair and apoptosis.

Discussion

We found that T. adhaerens are particularly resilient to DNA damage, which may explain why there have been no reports of cancer in placozoans. Mice die when exposed to 10 Gy of radiation [23,24]. Approximately 3 to 7 Gy of X-rays induces severe DNA damage in mammalian cells [25], and 6 Gy is almost always fatal for humans [26]. In contrast, cancer cell cultures exposed to a cumulative dose of 60 Gy develop radioresistance [27]. What is fascinating about T. adhaerens is that despite extensive DNA damage, they survive and fully recover, and, in the process, they extrude apparently damaged clusters of cells that eventually die.

T. adhaerens appear to be highly resistant to radiation We found that some T. adhaerens were able to survive extremely high levels (218.6 Gy) of radiation exposure. There are several possible mechanisms that might underlie this radiation resistance. Tardigrades are radioresistant due to mechanisms that prevent DNA damage in the first place [28,29], which seems to be an adaptation to dehydration [30]. Dehydration is unlikely to have been an issue for sea creatures like T. adhaerens, and their radiation resistance appears not to be due to preventing the DNA damage. In fact, T. adhaerens suffer extensive DNA damage from the X-rays but rely on mechanisms to repair DNA and maintain tissue homeostasis. Also, it is possible that their asexual reproductive strategy of budding reproduction might allow them to make use of many of the same mechanisms to extrude mutated cells in response to radiation exposure. T. adhaerens reproduce vegetatively by repartitioning cells into new individuals. This could expose the population to the risk of spreading cancer cells. Thomas and colleagues [31] propose that the prevention of transmissible cancer could be a factor in the evolution of sexual reproduction, which, combined with immune surveillance, facilitates the detection of a transmissible cancer. They hypothesize that ancient asexual lineages would have had to evolve alternative, efficient mechanisms to prevent cancer from spreading, and note that other ancient asexual organisms (bdelloid rotifers [32] and oribatid mites [33]) are resistant to ionizing radiation and heavy metals. Our results support their hypothesis. Cell extrusion may be one of those mechanisms predicted by Thomas and colleagues to protect ancient asexual organisms. Because there is no germline/soma distinction in T. adhaerens, sexual reproduction could expose an individual to develop gametes from somatic mutated cells or even cancer cells. They also lack an immune system to detect de novo or transmissible cancers. Because the disposable soma theory [34] does not apply to placozoans, there may have been strong selective pressure on them to develop alternate mechanisms of cancer suppression.

Expression of DNA repair genes and apoptotic pathways increases after radiation exposure T. adhaerens up-regulate genes involved in DNA repair, apoptosis, signaling, microtubule activity, transporters, stress response, and radioresistance (Table 1 and S1 Table). In particular, our detection of increased expression of the radioresistance gene TriadG28470 (EIF41B) is a nice (positive control) validation of our experimental approach. Interestingly, TriadG53566 (SMARCE1), a gene associated with chromatin remodeling complexes SWI/SNF, is also overexpressed. SWI/SNF complexes are involved in a variety of biological processes, including DNA repair. There is also evidence that SMARCE1 has a tumor suppressor function [35]. The other genes that were overexpressed after X-ray exposure, with unknown or poorly known functions may be related to DNA repair, tissue homeostasis, or apoptosis. For instance, Triad28044 is a homolog of the human gene EMC2. The function of EMC2 is not well known in humans, but our results suggest that at least one of its functions may be X-ray damage response. We also found that, after radiation exposure, MDM2, the negative regulator of TP53, is overexpressed in T. adhaerens, but TP53 expression does not increase. This may be an adaptation to prevent catastrophic levels of TP53-induced cell death after X-ray exposure, while the animal activates mechanisms of DNA and tissue repair. A possible interpretation of these results is that MDM2 represses TP53 activity soon after X-ray exposure. It is also possible that MDM2 has additional functions related to DNA repair [36]. Although MDM2 is well conserved in evolution, neither C. elegans nor D. melanogaster have MDM2 [22], suggesting that T. adhaerens may be a particularly good model for studying apoptosis.

T. adhaerens extrudes apparently damaged cells that subsequently die One striking mechanism we observed for dealing with potentially damaged and mutated cells is extrusion of those cells. With the small number of samples and the large number of mutations, we did not have enough statistical power to identify systematic differences in parental and extruded cells. We did detect an overabundance of mutations in apoptotic pathways, as well as overexpression of MDM2. This may be due to natural selection at the cellular level—cells with those mutations and responses would tend to survive, while cells that lacked those mutations and responses probably died. In T. adhaerens, X-ray exposure triggers cell extrusion, but the resulting buds are not a form of asexual reproduction. Initially, it is difficult to distinguish extrusion of inviable cells from asexual budding, and so the number of animals seems to increase soon after X-ray exposure. But, as we followed those buds, we found that they almost always die (Figs 3 and S2). This extrusion may be a tissue or organismal strategy to remove damaged cells from the main animal body. We hypothesize that this is a cancer suppression mechanism, extruding premalignant cells before they can threaten the organism. This capacity for extrusion of cells might be responsible for the absence of evidence of cancer in T. adhaerens. While the use of extrusion to prevent cancer may seem only relevant to simple organisms, the majority of human cancers arise in epithelial tissues, where extrusion and shedding of damaged cells could be a strategy for eliminating cancerous growths (such as the tissues of the skin and gut). There are hints that similar processes of extrusion of oncogenic cells may be at work in human cancer resistance [37–40]. Apoptotic cells and overproliferating cells can trigger extrusion [37–40]. The Sphingosine 1-Phosphate pathway contributes to its regulation and is accomplished through cytoskeleton remodeling [41]. The extrusion process is highly conserved in evolution [37–40]. Extrusion is involved in development, initiating cell differentiation, and epithelial–mesenchymal transitions in different organisms ranging from invertebrates to vertebrates [42]. Bacterial infection stimulates shedding, suggesting that cell extrusion is also a defensive mechanism against pathogens; in fact, bacteria can hijack the extrusion molecular mechanisms to invade underlying tissues [42]. Cell cooperation (signaling) and competition are 2 important factors in extrusion [42]. Cell competition is a cell elimination process through which cells can eliminate defective (for instance, growth rate and metabolic capacity) adjacent cells. The aberrant activation of signaling pathways in emergent cancer cells can be recognized by normal cells and triggers the elimination of the defective cells. Cell competition could have a key role in Placozoa because these simple animals have not evolved a complex tissue organization. The extrusion of damaged cells may be a manifestation of cell–cell policing, a process that involves both cell competition and the regulation of cellular cooperation. Extrusion of damaged cells is an understudied cancer suppression mechanism. At the moment, this process is only partially understood as it can only be studied in vivo in intact organisms. The opportunity to study cell extrusion in a simple animal model like T. adhaerens allows us to analyze the molecular mechanisms at the base of this process in detail. More broadly, extrusion may allow tissues to defend themselves against neoplastic cells; however, extrusion might also, in some cases, enable the spread of tumoral cellular aggregates in surrounding tissues and in the bloodstream, facilitating the formation of metastasis in advanced tumors. In fact, the metastatic efficiency of tumor cells increases when cells aggregate in multicellular clusters [43]. In this case, it is possible that what was originally a defense mechanism may be subverted by neoplasms in order to metastasize. Understanding this could potentially lead to interventions to help shed precancer cells, to prevent cancer, or alternatively, even suppress this extrusion process to help prevent metastasis.

Both T. adhaerens and extruded buds have high levels of mutation The extremely high levels of DNA fragmentation and mutations caused by X-ray radiation suggests that T. adhaerens is either very good at repairing DNA or is simply able to tolerate high rates of mutations. The genome sequencing of animals after 2 years from X-ray exposure showed the ability of T. adhaerens to survive, apparently without morphological or behavioral changes, harboring 72.7 total mutations in average. The number of mutations is strongly reduced compared to the number of mutations detected after 82 and 72 days from X-ray exposure, suggesting that the animals can remove mutations over time using a combination of cell extrusion and DNA repair mechanisms, suggesting a negative selection of mutated cells and a progressive process of DNA repair. To survive the initial extensive DNA damage, the organisms could activate mechanisms of DNA damage tolerance [44] and repair their DNA through subsequent DNA repair cycles. The activation of genes involved in repairing DNA double strand breaks through mechanisms of both homologous recombination (for instance, TriadG28563) and nonhomologous end-joining (for instance, TriadG61626) had a critical role in the extensive DNA damage recovery. We could hypothesize that other unknown genes overexpressed in response to DNA damage are involved in DNA repair as well. The simplicity of maintaining T. adhaerens in culture, the availability of their genome sequence, and molecular tools [20] will allow a rapid experimental validation of the function of these genes. We found a statistically significant enrichment of genes coding for NB-ARC domain-containing protein. There is only one human gene, APAF1, with the same protein domain but 68 on T. adhaerens. These genes could be involved in the regulation of apoptotic process [45]. The impairment of these genes could have a function in the X-ray damage resilience, inhibiting apoptosis, but at the same time, the abundance of these genes could have a role in preventing cancer development. Moreover, the activation of antiapoptotic genes (for instance, MDM2) may prevent damaged cells from dying. T. adhaerens may avoid a massive loss of cells due to the extensive damage induced by X-rays by repairing or eliminating the damaged cells over the long term. Importantly, these pathways are well known to be impaired in cancer cells, suggesting that T. adhaerens could be a good model to study the mechanisms of carcinogenesis and cancer radioresistance. The low number of samples sequenced do not allow us to draw conclusions pertaining to differences between the parental X-ray-exposed specimens and extrusions from the same individuals.

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