Damage Sensor Research Articles

Reduced FOXF1 links unrepaired DNA damage to pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) is a progressive disease in which pulmonary arterial (PA) endothelial cell (EC) dysfunction is associated with unrepaired DNA damage. BMPR2 is the most common genetic cause of PAH. We report that human PAEC with reduced BMPR2 have persistent DNA damage in room air after hypoxia (reoxygenation), as do mice with EC-specific deletion of Bmpr2 (EC-Bmpr2-/-) and persistent pulmonary hypertension. Similar findings are observed in PAEC with loss of the DNA damage sensor ATM, and in mice with Atm deleted in EC (EC-Atm-/-). Gene expression analysis of EC-Atm-/- and EC-Bmpr2-/- lung EC reveals reduced Foxf1, a transcription factor with selectivity for lung EC. Reducing FOXF1 in control PAEC induces DNA damage and impaired angiogenesis whereas transfection of FOXF1 in PAH PAEC repairs DNA damage and restores angiogenesis. Lung EC targeted delivery of Foxf1 to reoxygenated EC-Bmpr2-/- mice repairs DNA damage, induces angiogenesis and reverses pulmonary hypertension.

Impact of diffused versus vasculature targeted DNA damage on the heart of mice depleted of telomeric factor Ft1.

DNA damage is emerging as a driver of heart disease, although the cascade of events, its timing, and the cell types involved are yet to be fully clarified. In this context, the implication of cardiomyocytes has been highlighted, while that of vasculature smooth muscle cells has been implicated but not explored exhaustively. In our previous work we characterized a factor called Ft1 in mice and AKTIP in humans whose depletion generates telomere instability and DNA damage. Herein, we explored the effect of the reduction of Ft1 on the heart with the goal of comparatively defining the impact of DNA damage targeted to vasculature smooth muscle cells to that of diffuse damage. Using two newly generated mouse models, Ft1 constitutively knocked out (Ft1ko) mice, and mice in which we targeted the Ft1 depletion to the smooth muscle cells (Ft1sm22ko), it is shown that both genetic models display cardiac defects but with differences. Both Ft1ko and Ft1sm22ko mice display hypertrophy, fibrosis, and functional heart defects. Interestingly, Ft1sm22ko mice have early milder pathological traits that become manifest with age. Significantly, the defects of Ft1ko mice, including the alteration of the left ventricle and functional heart defects, are rescued by depletion of the DNA damage sensor p53. These results point to Ft1 deficiency as a driver of cardiac disease and show that Ft1 deficiency targeted to vasculature smooth muscle cells generates a pre-pathological profile exacerbated by age.

Mitf is a Schwann cell sensor of axonal integrity that drives nerve repair

Schwann cells respond to acute axon damage by transiently transdifferentiating into specialized repair cells that restore sensorimotor function. However, the molecular systems controlling repair cell formation and function are not well defined, and consequently, it is unclear whether this form of cellular plasticity has a role in peripheral neuropathies. Here, we identify Mitf as a transcriptional sensor of axon damage under the control of Nrg-ErbB-PI3K-PI5K-mTorc2 signaling. Mitf regulates a core transcriptional program for generating functional repair Schwann cells following injury and during peripheral neuropathies caused by CMT4J and CMT4D. In the absence of Mitf, core genes for epithelial-to-mesenchymal transition, metabolism, and dedifferentiation are misexpressed, and nerve repair is disrupted. Our findings demonstrate that Schwann cells monitor axonal health using a phosphoinositide signaling system that controls Mitf nuclear localization, which is critical for activating cellular plasticity and counteracting neural disease.

Single-cell transcriptomics reveals subtype-specific molecular profiles in Nrf2-deficient macrophages from murine atherosclerotic aortas.

Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcriptional regulator of antioxidant and anti-inflammatory response in all cell types. It also activates the transcription of genes important for macrophage function. Nrf2 activity declines with age and has been closely linked to atherosclerosis, but its specific role in this vascular pathology is not clear. Atherosclerotic plaques contain several macrophage subsets with distinct, yet not completely understood, functions in the lesion development. The aim of this study was to analyze the transcriptome of diverse Nrf2-deficient macrophage subpopulations from murine atherosclerotic aortas. Mice with transcriptionally inactive Nrf2 in Cdh5-expressing cells (Nrf2 Cdh5tKO) were used in the experiments. These mice lack transcriptional Nrf2 activity in endothelial cells, but also in a proportion of leukocytes. We confirmed that the bone marrow-derived and tissue-resident macrophages isolated from Nrf2 Cdh5tKO mice exhibit a significant decline in Nrf2 activity. Atherosclerosis was induced in Nrf2 Cdh5tKO and appropriate control mice via adeno-associated viral vector (AAV)-mediated overexpression of murine proprotein convertase subtilisin/kexin type 9 (Pcsk9) in the liver and high-fat diet feeding. After 21 weeks, live aortic cells were sorted on FACS and single-cell RNA sequencing (scRNA-seq) was performed. Unsupervised clustering singled out 13 distinct aortic cell types. Among macrophages, 9 subclusters were identified. Differential gene expression analysis revealed cell subtype-specific expression patterns. A subset of inflammatory macrophages from atherosclerotic Nrf2 Cdh5tKO mice demonstrated downregulation of DNA replication genes (e.g. Mcm7, Lig1, Pola1) concomitant with upregulation of DNA damage sensor Atr gene. Atherosclerotic Nrf2 Cdh5tKO Lyve1+ resident macrophages showed strong upregulation of IFN-stimulated genes, as well as changes in the expression of death pathways-associated genes (Slc40a1, Bcl2a1). Furthermore, we observed subtype-specific expression of core ferroptosis genes (e.g. Cp, Hells, Slc40a1) in inflammatory versus tissue resident macrophages. This observation suggested a link between ferroptosis and inflammatory microenvironment appearing at a very early stage of atherogenesis. Our findings indicate that Nrf2 deficiency in aortic macrophages leads to subtype-specific transcriptomic changes associated with inflammation, iron homeostasis, cell injury or death pathways. This may help understanding the role of aging-associated decline of Nrf2 activity and the function of specific macrophage subtypes in atherosclerotic lesion development.

DNA Damage Triggers the Activation of Immune Response to Viral Pathogens via Salicylic Acid in Plants.

Plants are challenged by various pathogens throughout their lives, such as bacteria, viruses, fungi, and insects; consequently, they have evolved several defense mechanisms. In addition, plants have developed localized and systematic immune responses due to biotic and abiotic stress exposure. Animals are known to activate DNA damage responses (DDRs) and DNA damage sensor immune signals in response to stress, and the process is well studied in animal systems. However, the links between stress perception and immune response through DDRs remain largely unknown in plants. To determine whether DDRs induce plant resistance to pathogens, Arabidopsis plants were treated with bleomycin, a DNA damage-inducing agent, and the replication levels of viral pathogens and growth of bacterial pathogens were determined. We observed that DDR-mediated resistance was specifically activated against viral pathogens, including turnip crinkle virus (TCV). DDR increased the expression level of pathogenesis-related (PR) genes and the total salicylic acid (SA) content and promoted mitogen-activated protein kinase signaling cascades, including the WRKY signaling pathway in Arabidopsis. Transcriptome analysis further revealed that defense- and SA-related genes were upregulated by DDR. The atm-2atr-2 double mutants were susceptible to TCV, indicating that the main DDR signaling pathway sensors play an important role in plant immune responses. In conclusion, DDRs activated basal immune responses to viral pathogens.

Longitudinal wave scattering in thin plates with symmetric damage considering oblique incidence

The interactions between ultrasonic waves and damage provide crucial information for developing effective damage detection techniques in various fields, including non-destructive testing and structural health monitoring, and they can be investigated through wave propagation. Then, this article presents an approach to investigate the longitudinal wave in thin plates with symmetric damage considering oblique incidence. The approach includes a strategy to determine the plate thickness reduction due to the damage presence by considering an oblique incidence of waves generated by the actuator. Modeling is developed to compute each wave packet of reflected and transmitted waves separately, which allows one to describe the wave scattering. Numerical simulations are carried out and the results show that the sensor size can be adjusted to improve the existence of damage detection and the determination of the damage depth. Results from experimental tests are presented to demonstrate the approach considering a circular actuator. The findings contribute to improving the comprehension of the interaction between guided waves and discontinuities, potentially encouraging the use of waves for damage sizing purposes rather than only for detection and improve the current state of the art in wave propagation by investigating the effects of different excitation frequencies and the influence of the damage parameters and sensor sizing on the resulting waves.

A computational model of the DNA damage-induced IKK/ NF-κB pathway reveals a critical dependence on irradiation dose and PARP-1

The activation of IKK/NF-κB by genotoxic stress is a crucial process in the DNA damage response. Due to the anti-apoptotic impact of NF-κB, it can affect cell-fate decisions upon DNA damage and therefore interfere with tumor therapy-induced cell death. Here, we developed a dynamical model describing IKK/NF-κB signaling that faithfully reproduces quantitative time course data and enables a detailed analysis of pathway regulation. The approach elucidates a pathway topology with two hubs, where the first integrates signals from two DNA damage sensors and the second forms a coherent feedforward loop. The analyses reveal a critical role of the sensor protein PARP-1 in the pathway regulation. Introducing a method for calculating the impact of changes in individual components on pathway activity in a time-resolved manner, we show how irradiation dose influences pathway activation. Our results give a mechanistic understanding relevant for the interpretation of experimental and clinical studies.

C. elegans Hemidesmosomes Sense Collagen Damage to Trigger Innate Immune Response in the Epidermis.

The collagens are an enormous family of extracellular matrix proteins that play dominant roles in cell adhesion, migration and tissue remodeling under many physiological and pathological conditions. However, their function mechanisms in regulating innate immunity remain largely undiscovered. Here we use C. elegans epidermis as the model to address this question. The C. elegans epidermis is covered with a collagen-rich cuticle exoskeleton and can produce antimicrobial peptides (AMPs) against invading pathogens or physical injury. Through an RNAi screen against collagen-encoding genes, we found that except the previously reported six DPY collagens and the BLI-1 collagen, the majority of collagens tested appear unable to trigger epidermal immune defense when damaged. Further investigation suggests that the six DPY collagens form a specific substructure, which regulates the interaction between BLI-1 and the hemidesmosome receptor MUP-4. The separation of BLI-1 with MUP-4 caused by collagen damage leads to the detachment of the STAT transcription factor-like protein STA-2 from hemidesmosomes and the induction of AMPs. Our findings uncover the mechanism how collagens are organized into a damage sensor and how the epidermis senses collagen damage to mount an immune defense.

Improving resilience of sensors in planetary exploration using data-driven models

Improving the resilience of sensor systems in space exploration is a key objective since the environmental conditions to which they are exposed are very harsh. For example, it is known that the presence of flying debris and Dust Devils on the Martian surface can partially damage sensors present in rovers/landers. The objective of this work is to show how data-driven methods can improve sensor resilience, particularly in the case of complex sensors, with multiple intermediate variables, feeding an inverse algorithm (IA) based on calibration data. The method considers three phases: an initial phase in which the sensor is calibrated in the laboratory and an IA is designed; a second phase, in which the sensor is placed at its intended location and sensor data is used to train data-driven model; and a third phase, once the model has been trained and partial damage is detected, in which the data-driven algorithm is reducing errors. The proposed method is tested with the intermediate data of the wind sensor of the TWINS instrument (NASA InSight mission), consisting of two booms placed on the deck of the lander, and three boards per boom. Wind speed and angle are recovered from the intermediate variables provided by the sensor and predicted by the proposed method. A comparative analysis of various data-driven methods including machine learning and deep learning (DL) methods is carried out for the proposed research. It is shown that even a simple method such as k-nearest neighbor is capable of successfully recovering missing data of a board compared to complex DL models. Depending on the selected missing board, errors are reduced by a factor between 2.43 and 4.78, for horizontal velocity; and by a factor between 1.74 and 4.71, for angle, compared with the situation of using only the two remaining boards.

A local ATR-dependent checkpoint pathway is activated by a site-specific replication fork block in human cells.

When replication forks encounter DNA lesions that cause polymerase stalling, a checkpoint pathway is activated. The ATR-dependent intra-S checkpoint pathway mediates detection and processing of sites of replication fork stalling to maintain genomic integrity. Several factors involved in the global checkpoint pathway have been identified, but the response to a single replication fork barrier (RFB) is poorly understood. We utilized the Escherichia coli-based Tus-Ter system in human MCF7 cells and showed that the Tus protein binding to TerB sequences creates an efficient site-specific RFB. The single fork RFB was sufficient to activate a local, but not global, ATR-dependent checkpoint response that leads to phosphorylation and accumulation of DNA damage sensor protein γH2AX, confined locally to within a kilobase of the site of stalling. These data support a model of local management of fork stalling, which allows global replication at sites other than the RFB to continue to progress without delay.

Ribosomal DNA copy number alteration in blood sample from gastric cancer patients.

Ribosomal DNA (rDNA) is the most abundant and important housekeeping gene in the cell. It usually acted as DNA damage sensor in DNA damage reaction. Gastric cancer (GC) as a tumor with high morbidity and mortality, it is hard to diagnosis in an early stage. In this study, we collected and test the copy number of rDNA in blood sample of 42 GC patients and 56 healthy controls (HC) to explore the relationship between rDNA and GC. Besides, we make a correlation between the copy number of rDNA and ten biomarkers (CYFR21-1, CA15-3, CA72-4, NSE, CEA, CA125, ProGRP, AFP, SCC, CA19-9). The copy number of 18S, 5.8S, 28S rDNA in GC is less than HC and 5S is more than HC in their blood sample. And the expression of H-cox-1 and ND1 in GC is higher than HC in blood sample. it shows the expression of CA15-3 is related to ND1 and H-cox-1. We found for the first time the changes of rDNA and mtDNA expression in the blood of patients with gastric cancer. All these finding suggests rDNA may have potential in diagnosing GC.

UV-DDB as a General Sensor of DNA Damage in Chromatin: Multifaceted Approaches to Assess Its Direct Role in Base Excision Repair.

Base excision repair (BER) is a cellular process that removes damaged bases arising from exogenous and endogenous sources including reactive oxygen species, alkylation agents, and ionizing radiation. BER is mediated by the actions of multiple proteins which work in a highly concerted manner to resolve DNA damage efficiently to prevent toxic repair intermediates. During the initiation of BER, the damaged base is removed by one of 11 mammalian DNA glycosylases, resulting in abasic sites. Many DNA glycosylases are product-inhibited by binding to the abasic site more avidly than the damaged base. Traditionally, apurinic/apyrimidinic endonuclease 1, APE1, was believed to help turn over the glycosylases to undergo multiple rounds of damaged base removal. However, in a series of papers from our laboratory, we have demonstrated that UV-damaged DNA binding protein (UV-DDB) stimulates the glycosylase activities of human 8-oxoguanine glycosylase (OGG1), MUTY DNA glycosylase (MUTYH), alkyladenine glycosylase/N-methylpurine DNA glycosylase (AAG/MPG), and single-strand selective monofunctional glycosylase (SMUG1), between three- and five-fold. Moreover, we have shown that UV-DDB can assist chromatin decompaction, facilitating access of OGG1 to 8-oxoguanine damage in telomeres. This review summarizes the biochemistry, single-molecule, and cell biology approaches that our group used to directly demonstrate the essential role of UV-DDB in BER.

Luminescence characteristics of white light emitting BaGa2O4:Dy3+ phosphors for LEDs and stress sensing applications

A series of single-phase white-light-emitting BaGa2O4:xDy3+(x = 0.1,0.3,0.5,0.7,1) phosphors have been synthesised using solid-state reaction technique. The structural studies using the X-ray diffraction (XRD) technique indicate that the phosphors are single-phase and Scanning Electron Microscope (SEM) study reveals that the particle size is in micrometer range. The phosphors emit white light with peaks at 346 nm, 357 nm, 386 nm, and 426 nm generated by Dy3+ ion transitions (6H15/2 → 6P7/2), (6H15/2 → 6P9/2), (6H15/2 → 4F7/2+4I13/2) and (6H15/2 → 4G11/2). The colour coordinates calculated for BaGa2O4:xDy3+ (x = 0.5,0.7) phosphors are identical to the conventional white light. BaGa2O4:Dy3+ exhibits good Mechanoluminescence (ML) response at varied impact velocities for both unirradiated and gamma-irradiated samples. This characteristic is reasonably beneficial in the development of damage and pressure sensors. Thermoluminescence (TL) analysis shows a single glow curve of similar shape irrespective of increasing irradiation, and the TL parameters have been calculated.

Event‐triggered attack detection and state estimation based on Gaussian mixture model

AbstractUnder the framework of event‐triggered transmission mechanism, the problem of attack detection and state estimation of multi‐sensor linear time‐invariant systems under static attacks is considered. First, for each transmission channel, the sensor collects measurement information according to an event‐triggered mechanism to reduce unnecessary energy consumption. Then, inspired by the clustering algorithm in machine learning, a detection mechanism based on Gaussian mixture model, which can set a confidence level for the measurement of each sensor is proposed. Finally, centralised data fusion is performed according to the results of attack detection and event‐triggered judgement to realise remote state estimation. A numerical example proves that the proposed algorithm can locate the damaged sensor, save the network transmission bandwidth under the premise of ensuring accuracy and efficiency of sensor estimation.

DSC‐based finite‐time adaptive resilient control for a class of nonstrict‐feedback switched nonlinear systems with deception attacks

AbstractIn this paper, the finite‐time adaptive resilient control problem for a class of switched nonlinear systems with deception attacks by using the dynamic surface control (DSC) strategy is addressed. A more general class of uncertain nonstrict‐feedback switched nonlinear systems with the sensor and actuator deception attacks are considered. Deception attacks can damage sensor, control and switching data, which results in the switching signal and the finite‐time control gains unknown, meanwhile the conventional dynamic surface errors inacessible. To overcome the difficulty, first, the approximation technique of neural networks (NNs) is used to deal with the unknown nonlinear terms and compensate the sensor and actuator deception attacks. Secondly, a new coordinate transformation and a novel switched adaptive finite‐time filter are designed to mitigate the effects caused by the sensor attacks and avoid the problem of “explosion of complexity”. Thirdly, Nussbaum technology is exploited to handle the unknown finite‐time control gains problem caused by deception attacks. Then, by the proposed control strategy, the practical finite‐time stability analysis is presented. Finally, a simulation example is provided to validate the feasibility of the proposed control method.

HR repair pathway plays a crucial role in maintaining neural stem cell fate under irradiation stress.

Environmental stress can cause mutation or genomic instability in stem cells which, in some cases, leads to tumorigenesis. Mechanisms to monitor and eliminate these mutant stem cells remain elusive. Here, using the Drosophila larval brain as a model, we show that X-ray irradiation (IR) at the early larval stage leads to accumulation of nuclear Prospero (Pros), resulting in premature differentiation of neural stem cells (neuroblasts, NBs). Through NB-specific RNAi screenings, we determined that it is the Mre11-Rad50-Nbs1 complex and the homologous recombination (HR) repair pathway, rather than non-homologous end-joining pathway that plays, a dominant role in the maintenance of NBs under IR stress. The DNA damage sensor ATR/mei-41 is shown to act to prevent IR-induced nuclear Pros in a WRNexo-dependent manner. The accumulation of nuclear Pros in NBs under IR stress, leads to NB cell fate termination, rather than resulting in mutant cell proliferation. Our study reveals an emerging mechanism for the HR repair pathway in maintaining neural stem cell fate under irradiation stress.

Structural and functional analyses of the echinomycin resistance conferring protein Ecm16 from Streptomyces lasalocidi

Echinomycin is a natural product DNA bisintercalator antibiotic. The echinomycin biosynthetic gene cluster in Streptomyces lasalocidi includes a gene encoding the self-resistance protein Ecm16. Here, we present the 2.0 Å resolution crystal structure of Ecm16 bound to adenosine diphosphate. The structure of Ecm16 closely resembles that of UvrA, the DNA damage sensor component of the prokaryotic nucleotide excision repair system, but Ecm16 lacks the UvrB-binding domain and its associated zinc-binding module found in UvrA. Mutagenesis study revealed that the insertion domain of Ecm16 is required for DNA binding. Furthermore, the specific amino acid sequence of the insertion domain allows Ecm16 to distinguish echinomycin-bound DNA from normal DNA and link substrate binding to ATP hydrolysis activity. Expression of ecm16 in the heterologous host Brevibacillus choshinensis conferred resistance against echinomycin and other quinomycin antibiotics, including thiocoraline, quinaldopeptin, and sandramycin. Our study provides new insight into how the producers of DNA bisintercalator antibiotics fend off the toxic compounds that they produce.

RNAi screening for modulators of an osmo-sensitive gene response to extracellular matrix damage reveals negative feedback and interactions with translation inhibition.

In epidermal tissues, extracellular matrices (ECMs) function as barriers between the organism and environment. Despite being at the interface with the environment, little is known about the role of animal barrier ECMs in sensing stress and communicating with cytoprotective gene pathways in neighboring cells. We and others have identified a putative damage sensor in the C. elegans cuticle that regulates osmotic, detoxification, and innate immune response genes. This pathway is associated with circumferential collagen bands called annular furrows; mutation or loss of furrow collagens causes constitutive activation of osmotic, detoxification, and innate immune response genes. Here, we performed a genome-wide RNAi screen for modulators of osmotic stress response gene gpdh-1 in a furrow collagen mutant strain. RNAi of six genes identified in this screen were tested under other conditions and for effects on other stress responses. The functions of these genes suggest negative feedback within osmolyte accumulation pathways and interactions with ATP homeostasis and protein synthesis. Loss of these gpdh-1 modulators had distinct effects on canonical detoxification and innate immune response genes.

PTEN-negative endometrial cancer cells protect their genome through enhanced DDB2 expression associated with augmented nucleotide excision repair

BackgroundEndometrial cancer (EC) arises from uterine endometrium tissue and is the most prevalent cancer of the female reproductive tract in developed countries. It has been predicted that the global prevalence of EC will increase in part because of its positive association with economic growth and lifestyle. The majority of EC presented with endometrioid histology and mutations in the tumor suppressor gene PTEN, resulting in its loss of function. PTEN negatively regulates the PI3K/Akt/mTOR axis of cell proliferation and thus serves as a tumorigenesis gatekeeper. Through its chromatin functions, PTEN is also implicated in genome maintenance procedures. However, our comprehension of how DNA repair occurs in the absence of PTEN function in EC is inadequate.MethodsWe utilized The Cancer Genome Atlas (TCGA) data analysis to establish a correlation between PTEN and DNA damage response genes in EC, followed by a series of cellular and biochemical assays to elucidate a molecular mechanism utilizing the AN3CA cell line model for EC.ResultsThe TCGA analyses demonstrated an inverse correlation between the expression of the damage sensor protein of nucleotide excision repair (NER), DDB2, and PTEN in EC. The transcriptional activation of DDB2 is mediated by the recruitment of active RNA polymerase II to the DDB2 promoter in the PTEN-null EC cells, revealing a correlation between increased DDB2 expression and augmented NER activity in the absence of PTEN.ConclusionOur study indicated a causal relationship between NER and EC that may be exploited in disease management.

The DNA Damage Sensor MRE11 Regulates Efficient Replication of the Autonomous Parvovirus Minute Virus of Mice.

Parvoviruses are single-stranded DNA viruses that utilize host proteins to vigorously replicate in the nuclei of host cells, leading to cell cycle arrest. The autonomous parvovirus, minute virus of mice (MVM), forms viral replication centers in the nucleus which are adjacent to cellular DNA damage response (DDR) sites, many of which are fragile genomic regions prone to undergoing DDR during the S phase. Since the cellular DDR machinery has evolved to transcriptionally suppress the host epigenome to maintain genomic fidelity, the successful expression and replication of MVM genomes at these cellular sites suggest that MVM interacts with DDR machinery distinctly. Here, we show that efficient replication of MVM requires binding of the host DNA repair protein MRE11 in a manner that is independent of the MRE11-RAD50-NBS1 (MRN) complex. MRE11 binds to the replicating MVM genome at the P4 promoter, remaining distinct from RAD50 and NBS1, which associate with cellular DNA break sites to generate DDR signals in the host genome. Ectopic expression of wild-type MRE11 in CRISPR knockout cells rescues virus replication, revealing a dependence on MRE11 for efficient MVM replication. Our findings suggest a new model utilized by autonomous parvoviruses to usurp local DDR proteins that are crucial for viral pathogenesis and distinct from those of dependoparvoviruses, like adeno-associated virus (AAV), which require a coinfected helper virus to inactivate the local host DDR. IMPORTANCE The cellular DNA damage response (DDR) machinery protects the host genome from the deleterious consequences of DNA breaks and recognizes invading viral pathogens. DNA viruses that replicate in the nucleus have evolved distinct strategies to evade or usurp these DDR proteins. We have discovered that the autonomous parvovirus, MVM, which is used to target cancer cells as an oncolytic agent, depends on the initial DDR sensor protein MRE11 to express and replicate efficiently in host cells. Our studies reveal that the host DDR interacts with replicating MVM molecules in ways that are distinct from viral genomes being recognized as simple broken DNA molecules. These findings suggest that autonomous parvoviruses have evolved distinct mechanisms to usurp DDR proteins, which can be used to design potent DDR-dependent oncolytic agents.