The Multiple Faces of the MRN Complex: Roles in Medulloblastoma and Beyond

Hypomorphic mutations in MRN complex genes are frequently found in cancer, supporting their role as oncosuppressors. However, unlike canonical oncosuppressors, MRN proteins are often overexpressed in tumor tissues, where they actively work to counteract DSBs induced by both oncogene-dependent RS and radio-chemotherapy. Moreover, at the same time, MRN genes are also essential genes, since the constitutive KO of each component leads to embryonic lethality. Therefore, even though it is paradoxical, MRN genes may work as oncosuppressive, oncopromoting, and essential genes. In this review, we discussed how alterations in the MRN complex impact the physiopathology of cancer, in light of our recent discoveries on the gene–dosage-dependent effect of NBS1 in Medulloblastoma. These updates aim to understand whether MRN complex can be realistically used as a prognostic/predictive marker and/or as a therapeutic target for the treatment of cancer patients in the future.

[1]  R. Piro,et al.  Simultaneous Nbs1 and p53 inactivation in neural progenitors triggers high‐grade gliomas , 2023, Neuropathology and applied neurobiology.

[2]  J. Petrini,et al.  ISG15: A link between innate immune signaling, DNA replication, and genome stability , 2023, BioEssays : news and reviews in molecular, cellular and developmental biology.

[3]  J. Petrini,et al.  ISG15 conjugation to proteins on nascent DNA mitigates DNA replication stress , 2022, Nature Communications.

[4]  G. Shapiro,et al.  Targeting replication stress in cancer therapy , 2022, Nature Reviews Drug Discovery.

[5]  Y. Pommier,et al.  Requirements for MRN endonuclease processing of topoisomerase II-mediated DNA damage in mammalian cells , 2022, Frontiers in Molecular Biosciences.

[6]  J. Nickoloff.  Targeting Replication Stress Response Pathways to Enhance Genotoxic Chemo- and Radiotherapy , 2022, Molecules.

[7]  E. Rakha,et al.  Targeting Mre11 overcomes platinum resistance and induces synthetic lethality in XRCC1 deficient epithelial ovarian cancers , 2022, npj Precision Oncology.

[8]  L. Di Marcotullio,et al.  A gene dosage‐dependent effect unveils NBS1 as both a haploinsufficient tumour suppressor and an essential gene for SHH‐medulloblastoma , 2022, Neuropathology and applied neurobiology.

[9]  A. Green,et al.  Untangling the clinicopathological significance of MRE11-RAD50-NBS1 complex in sporadic breast cancers , 2021, NPJ breast cancer.

[10]  Zhaojian Liu,et al.  Rad50 promotes ovarian cancer progression through NF‐κB activation , 2021, Journal of cellular and molecular medicine.

[11]  N. Sharma,et al.  The Safe Path at the Fork: Ensuring Replication-Associated DNA Double-Strand Breaks are Repaired by Homologous Recombination , 2021, Frontiers in Genetics.

[12]  E. Cacan,et al.  Involvement of ATMIN-DYNLL1-MRN axis in the progression and aggressiveness of serous ovarian cancer. , 2021, Biochemical and biophysical research communications.

[13]  S. Jiang,et al.  MRE11 promotes oral cancer progression through RUNX2/CXCR4/AKT/FOXA2 signaling in a nuclease-independent manner , 2021, Oncogene.

[14]  Ji Luo.  KRAS mutation in pancreatic cancer. , 2021, Seminars in oncology.

[15]  Y. Shiloh,et al.  Regulation of MRE11A by UBQLN4 leads to cisplatin resistance in patients with esophageal squamous cell carcinoma , 2021, Molecular oncology.

[16]  M. Biffoni,et al.  Control of replication stress and mitosis in colorectal cancer stem cells through the interplay of PARP1, MRE11 and RAD51 , 2021, Cell Death & Differentiation.

[17]  L. Górecki,et al.  Clinical Candidates Targeting the ATR–CHK1–WEE1 Axis in Cancer , 2021, Cancers.

[18]  A. Kiltie,et al.  SPRTN protease-cleaved MRE11 decreases DNA repair and radiosensitises cancer cells , 2021, Cell Death & Disease.

[19]  E. Rakha,et al.  Clinicopathological and Functional Evaluation Reveal NBS1 as a Predictor of Platinum Resistance in Epithelial Ovarian Cancers , 2021, Biomedicines.

[20]  Jun Huang,et al.  MRN complex is an essential effector of DNA damage repair , 2021, Journal of Zhejiang University-SCIENCE B.

[21]  E. Rakha,et al.  RAD50 deficiency is a predictor of platinum sensitivity in sporadic epithelial ovarian cancers , 2020, Molecular Biomedicine.

[22]  Q. Zhan,et al.  A Comprehensive Analysis of Alterations in DNA Damage Repair Pathways Reveals a Potential Way to Enhance the Radio-Sensitivity of Esophageal Squamous Cell Cancer , 2020, Frontiers in Oncology.

[23]  A. Lyakhovich,et al.  Enhanced DNA damage response through RAD50 in triple negative breast cancer resistant and cancer stem‐like cells contributes to chemoresistance , 2020, The FEBS journal.

[24]  A. Barzilai,et al.  NBS1 interacts with Notch signaling in neuronal homeostasis , 2020, Nucleic acids research.

[25]  J. Adjaye,et al.  Impaired p53-Mediated DNA Damage Response Contributes to Microcephaly in Nijmegen Breakage Syndrome Patient-Derived Cerebral Organoids , 2020, bioRxiv.

[26]  H. Hua,et al.  LncRNA SLC26A4-AS1 suppresses the MRN complex-mediated DNA repair signaling and thyroid cancer metastasis by destabilizing DDX5 , 2020, Oncogene.

[27]  Lisle E. Mose,et al.  A P53-Independent DNA Damage Response Suppresses Oncogenic Proliferation and Genome Instability. , 2020, Cell reports.

[28]  Hong Zhang,et al.  Prognostic Heterogeneity of MRE11 Based on the Location of Primary Colorectal Cancer Is Caused by Activation of Different Immune Signals , 2020, Frontiers in Oncology.

[29]  L. K. Teixeira,et al.  DNA replication stress: oncogenes in the spotlight , 2019, Genetics and Molecular Biology.

[30]  G. Giannini,et al.  SMO-M2 mutation does not support cell-autonomous Hedgehog activity in cerebellar granule cell precursors , 2019, Scientific Reports.

[31]  Meichao Zhang,et al.  MRE11-RAD50-NBS1 complex alterations and DNA damage response: implications for cancer treatment , 2019, Molecular Cancer.

[32]  R. Medzhitov,et al.  Harnessing innate immunity in cancer therapy , 2019, Nature.

[33]  N. Willis,et al.  DNA double-strand break repair-pathway choice in somatic mammalian cells , 2019, Nature Reviews Molecular Cell Biology.

[34]  M. Stern,et al.  Three new cases of ataxia‐telangiectasia‐like disorder: No impairment of the ATM pathway, but S‐phase checkpoint defect , 2019, Human mutation.

[35]  R. Fehrmann,et al.  Cyclin E expression is associated with high levels of replication stress in triple-negative breast cancer , 2019, npj Breast Cancer.

[36]  Junjie Chen,et al.  Mitosis-specific MRN complex promotes a mitotic signaling cascade to regulate spindle dynamics and chromosome segregation , 2018, Proceedings of the National Academy of Sciences.

[37]  Joseph V Bonventre,et al.  Prediction of DNA Repair Inhibitor Response in Short-Term Patient-Derived Ovarian Cancer Organoids. , 2018, Cancer discovery.

[38]  Mark T Lee,et al.  Overexpression of the MRE11-RAD50-NBS1 (MRN) complex in rectal cancer correlates with poor response to neoadjuvant radiotherapy and prognosis , 2018, BMC Cancer.

[39]  L. Di Marcotullio,et al.  MRE11 inhibition highlights a replication stress-dependent vulnerability of MYCN-driven tumors , 2018, Cell Death & Disease.

[40]  S. Lees-Miller,et al.  DNA-dependent protein kinase promotes DNA end processing by MRN and CtIP , 2018, Science Advances.

[41]  I. Vitale,et al.  Replication stress response in cancer stem cells as a target for chemotherapy. , 2018, Seminars in cancer biology.

[42]  K. Kurian,et al.  Replication Stress Drives Constitutive Activation of the DNA Damage Response and Radioresistance in Glioblastoma Stem-like Cells. , 2018, Cancer research.

[43]  Daniel G. Anderson,et al.  MicroRNA regulation of the MRN complex impacts DNA damage, cellular senescence, and angiogenic signaling , 2018, Cell Death & Disease.

[44]  S. Sengupta,et al.  MRN complex-dependent recruitment of ubiquitylated BLM helicase to DSBs negatively regulates DNA repair pathways , 2018, Nature Communications.

[45]  T. Crawford,et al.  Chromosome instability syndromes , 2018, Nature Reviews Disease Primers.

[46]  S. Miyano,et al.  Loss of DNA Damage Response in Neuroblastoma and Utility of a PARP Inhibitor , 2017, Journal of the National Cancer Institute.

[47]  Jing Wang,et al.  RAD50 Expression Is Associated with Poor Clinical Outcomes after Radiotherapy for Resected Non–small Cell Lung Cancer , 2017, Clinical Cancer Research.

[48]  D. Ferguson,et al.  MRE11 Promotes Tumorigenesis by Facilitating Resistance to Oncogene-Induced Replication Stress. , 2017, Cancer research.

[49]  J. Adjaye,et al.  Nijmegen Breakage Syndrome fibroblasts and iPSCs: cellular models for uncovering disease-associated signaling pathways and establishing a screening platform for anti-oxidants , 2017, Scientific Reports.

[50]  R. Płoski,et al.  The germline variants in DNA repair genes in pediatric medulloblastoma: a challenge for current therapeutic strategies , 2017, BMC Cancer.

[51]  H. Moch,et al.  Lack of MRE11-RAD50-NBS1 (MRN) complex detection occurs frequently in low-grade epithelial ovarian cancer , 2017, BMC Cancer.

[52]  Mark T Lee,et al.  MRE11 and ATM Expression Levels Predict Rectal Cancer Survival and Their Association with Radiotherapy Response , 2016, PloS one.

[53]  Nguyen Ngoc Hoa,et al.  Mre11 Is Essential for the Removal of Lethal Topoisomerase 2 Covalent Cleavage Complexes. , 2016, Molecular cell.

[54]  T. Oyama,et al.  High Expression of MRE11-RAD50-NBS1 Is Associated with Poor Prognosis and Chemoresistance in Gastric Cancer. , 2016, Anticancer research.

[55]  N. Benvenisty,et al.  Chromosomal Instability and Molecular Defects in Induced Pluripotent Stem Cells from Nijmegen Breakage Syndrome Patients. , 2016, Cell reports.

[56]  Sabine Petry.  Mechanisms of Mitotic Spindle Assembly. , 2016, Annual review of biochemistry.

[57]  Jun Huang,et al.  DNA End Resection: Facts and Mechanisms , 2016, Genom. Proteom. Bioinform..

[58]  Gehua Zhang,et al.  Targeting Rad50 sensitizes human nasopharyngeal carcinoma cells to radiotherapy , 2016, BMC Cancer.

[59]  G. Giannini,et al.  A MYCN-MRN complex axis controls replication stress for the safe expansion of neuroprogenitor cells , 2016, Molecular & cellular oncology.

[60]  H. Kato,et al.  Expression of DNA double-strand break repair proteins predicts the response and prognosis of colorectal cancer patients undergoing oxaliplatin-based chemotherapy. , 2016, Oncology reports.

[61]  J. Gautier,et al.  MRN, CtIP, and BRCA1 mediate repair of topoisomerase II–DNA adducts , 2016, The Journal of cell biology.

[62]  Hong Zhang,et al.  Prognostic Significance and Molecular Features of Colorectal Mucinous Adenocarcinomas , 2015, Medicine.

[63]  S. Kyo,et al.  CCNE1 amplification is associated with aggressive potential in endometrioid endometrial carcinomas , 2015, International journal of oncology.

[64]  N. Park,et al.  Clinicopathological values of NBS1 and DNA damage response genes in epithelial ovarian cancers , 2015, Experimental & Molecular Medicine.

[65]  S. Iannaccone,et al.  p53 modulates the activity of the GLI1 oncogene through interactions with the shared coactivator TAF9. , 2015, DNA repair.

[66]  C. O'Shea,et al.  Viral and Cellular Genomes Activate Distinct DNA Damage Responses , 2015, Cell.

[67]  Martin Vingron,et al.  Comprehensive genomic profiles of small cell lung cancer , 2015, Nature.

[68]  L. Di Marcotullio,et al.  The MRN complex is transcriptionally regulated by MYCN during neural cell proliferation to control replication stress , 2015, Cell Death and Differentiation.

[69]  A. Aguilera,et al.  Replication stress and cancer , 2015, Nature Reviews Cancer.

[70]  W. Abuzeid,et al.  Dual Disruption of DNA Repair and Telomere Maintenance for the Treatment of Head and Neck Cancer , 2014, Clinical Cancer Research.

[71]  H. Moch,et al.  Effect of MRE11 Loss on PARP-Inhibitor Sensitivity in Endometrial Cancer In Vitro , 2014, PloS one.

[72]  H. Leonhardt,et al.  Rad50-CARD9 interactions link cytosolic DNA sensing to IL-1β production , 2014, Nature Immunology.

[73]  T. Dörk,et al.  RAD50 phosphorylation promotes ATR downstream signaling and DNA restart following replication stress. , 2014, Human molecular genetics.

[74]  P. Jeggo,et al.  Dna Repair , 2022 .

[75]  L. McPherson,et al.  Poly (ADP-ribose) polymerase inhibitor LT-626: Sensitivity correlates with MRE11 mutations and synergizes with platinums and irinotecan in colorectal cancer cells. , 2014, Cancer letters.

[76]  Zhao-Qi Wang,et al.  The essential function of the MRN complex in the resolution of endogenous replication intermediates. , 2014, Cell reports.

[77]  S. Bhattarai,et al.  Post-transcriptional regulation of MRE11 expression in muscle-invasive bladder tumours , 2014, Oncotarget.

[78]  John A Tainer,et al.  DNA double-strand break repair pathway choice is directed by distinct MRE11 nuclease activities. , 2014, Molecular cell.

[79]  K. Cimprich,et al.  Causes and consequences of replication stress , 2013, Nature Cell Biology.

[80]  W. Tong,et al.  Mutation Inactivation of Nijmegen Breakage Syndrome Gene (NBS1) in Hepatocellular Carcinoma and Intrahepatic Cholangiocarcinoma , 2013, PloS one.

[81]  I. Screpanti,et al.  PCAF ubiquitin ligase activity inhibits Hedgehog/Gli1 signaling in p53-dependent response to genotoxic stress , 2013, Cell Death and Differentiation.

[82]  N. Curtin,et al.  Microsatellite instability induced mutations in DNA repair genes CtIP and MRE11 confer hypersensitivity to poly (ADP-ribose) polymerase inhibitors in myeloid malignancies , 2013, Haematologica.

[83]  David T. W. Jones,et al.  Subgroup-specific prognostic implications of TP53 mutation in medulloblastoma. , 2013, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[84]  A. Bowie,et al.  Immune sensing of DNA. , 2013, Immunity.

[85]  W. Dunphy,et al.  The Mre11-Rad50-Nbs1 (MRN) complex has a specific role in the activation of Chk1 in response to stalled replication forks , 2013, Molecular biology of the cell.

[86]  Alessandro Costa,et al.  DNA replication and homologous recombination factors: acting together to maintain genome stability , 2013, Chromosoma.

[87]  Shaun E. Peterson,et al.  The MRN-CtIP pathway is required for metaphase chromosome alignment. , 2013, Molecular cell.

[88]  Jiri Bartek,et al.  Replication stress links structural and numerical cancer chromosomal instability , 2013, Nature.

[89]  K. Ishii,et al.  DNA damage sensor MRE11 recognizes cytosolic double-stranded DNA and induces type I interferon by regulating STING trafficking , 2013, Proceedings of the National Academy of Sciences.

[90]  Arndt Hartmann,et al.  Expression of TIP60 (tat‐interactive protein) and MRE11 (meiotic recombination 11 homolog) predict treatment‐specific outcome of localised invasive bladder cancer , 2012, BJU international.

[91]  J. Bartek,et al.  Evaluation of candidate biomarkers to predict cancer cell sensitivity or resistance to PARP-1 inhibitor treatment , 2012, Cell cycle.

[92]  M. Hou,et al.  Role of MRE11 in cell proliferation, tumor invasion, and DNA repair in breast cancer. , 2012, Journal of the National Cancer Institute.

[93]  Nicholas J. Wang,et al.  Cross-platform pathway-based analysis identifies markers of response to the PARP inhibitor olaparib , 2012, Breast Cancer Research and Treatment.

[94]  T. Chou,et al.  Prognostic Significance of NBS1 and Snail Expression in Esophageal Squamous Cell Carcinoma , 2012, Annals of Surgical Oncology.

[95]  F. Hamdy,et al.  Mre11-dependent degradation of stalled DNA replication forks is prevented by BRCA2 and PARP1. , 2012, Cancer research.

[96]  S. Jackson,et al.  Structural biology of the Mre11:Nbs1 complex structure yields insights into ataxia–telangiectasia–like disease mutations and DNA damage signaling , 2012, Nature Structural &Molecular Biology.

[97]  B. McKay,et al.  Enhanced cytotoxicity of PARP inhibition in mantle cell lymphoma harbouring mutations in both ATM and p53 , 2012, EMBO molecular medicine.

[98]  J. Park,et al.  Associations between polymorphisms in DNA repair genes and TP53 mutations in non-small cell lung cancer. , 2011, Lung Cancer.

[99]  Benjamin J. Raphael,et al.  Integrated Genomic Analyses of Ovarian Carcinoma , 2011, Nature.

[100]  S. Gruber,et al.  MRE11 deficiency increases sensitivity to poly(ADP-ribose) polymerase inhibition in microsatellite unstable colorectal cancers. , 2011, Cancer research.

[101]  S. Matsuura,et al.  Two unrelated patients with MRE11A mutations and Nijmegen breakage syndrome-like severe microcephaly. , 2011, DNA repair.

[102]  Kou-Juey Wu,et al.  Induction of HSPA4 and HSPA14 by NBS1 overexpression contributes to NBS1-induced in vitro metastatic and transformation activity , 2011, Journal of Biomedical Science.

[103]  H. Ochs,et al.  Impaired induction of DNA lesions during immunoglobulin class-switch recombination in humans influences end-joining repair , 2010, Proceedings of the National Academy of Sciences.

[104]  M. Lopes,et al.  Rad51 protects nascent DNA from Mre11 dependent degradation and promotes continuous DNA synthesis , 2010, Nature Structural &Molecular Biology.

[105]  Ananya Choudhury,et al.  MRE11 expression is predictive of cause-specific survival following radical radiotherapy for muscle-invasive bladder cancer. , 2010, Cancer research.

[106]  M. Weitzman,et al.  The MRN complex in double‐strand break repair and telomere maintenance , 2010, FEBS letters.

[107]  Kou-Juey Wu,et al.  Identification of increased NBS1 expression as a prognostic marker of squamous cell carcinoma of the oral cavity , 2010, Cancer science.

[108]  K. Chrzanowska,et al.  Heterozygous germ-line mutations in the NBN gene predispose to medulloblastoma in pediatric patients , 2010, Acta Neuropathologica.

[109]  R. Reis,et al.  Analysis of microsatellite instability in medulloblastoma. , 2009, Neuro-oncology.

[110]  G. Oakley,et al.  Physical interaction between replication protein A (RPA) and MRN: involvement of RPA2 phosphorylation and the N-terminus of RPA1. , 2009, Biochemistry.

[111]  T. de Lange,et al.  Cell Cycle-Dependent Role of MRN at Dysfunctional Telomeres: ATM Signaling-Dependent Induction of Nonhomologous End Joining (NHEJ) in G1 and Resection-Mediated Inhibition of NHEJ in G2 , 2009, Molecular and Cellular Biology.

[112]  T. Dörk,et al.  Human RAD50 deficiency in a Nijmegen breakage syndrome-like disorder. , 2009, American journal of human genetics.

[113]  J. Kobayashi,et al.  Inactivation of the Nijmegen breakage syndrome gene leads to excess centrosome duplication via the ATR/BRCA1 pathway. , 2009, Cancer research.

[114]  T. Pandita,et al.  MRN complex function in the repair of chromosomal Rag-mediated DNA double-strand breaks , 2009, The Journal of experimental medicine.

[115]  A. Ruiz i Altaba,et al.  A GLI1-p53 inhibitory loop controls neural stem cell and tumour cell numbers , 2009, The EMBO journal.

[116]  S. Baker,et al.  Recurrent genomic alterations characterize medulloblastoma arising from DNA double-strand break repair deficiency , 2009, Proceedings of the National Academy of Sciences.

[117]  Michel Mittelbronn,et al.  Mutational Inactivation of the Nijmegen Breakage Syndrome Gene (NBS1) in Glioblastomas Is Associated With Multiple TP53 Mutations , 2009, Journal of neuropathology and experimental neurology.

[118]  M. J. Neale,et al.  Distinct requirements for the Rad32(Mre11) nuclease and Ctp1(CtIP) in the removal of covalently bound topoisomerase I and II from DNA. , 2009, Molecular cell.

[119]  Hong Zhang,et al.  RAD50/MRE11/NBS1 proteins in relation to tumour development and prognosis in patients with microsatellite stable colorectal cancer. , 2008, Histology and histopathology.

[120]  S. Moertl,et al.  NBS1 is required for IGF-1 induced cellular proliferation through the Ras/Raf/MEK/ERK cascade. , 2008, Cellular signalling.

[121]  D. Ferguson,et al.  Mre11 Nuclease Activity Has Essential Roles in DNA Repair and Genomic Stability Distinct from ATM Activation , 2008, Cell.

[122]  C. Cordon-Cardo,et al.  Chk2 suppresses the oncogenic potential of DNA replication-associated DNA damage. , 2008, Molecular cell.

[123]  H. Ohgaki,et al.  Mutations in the Nijmegen Breakage Syndrome Gene in Medulloblastomas , 2008, Clinical Cancer Research.

[124]  Nobuyuki Tanaka,et al.  Hedgehog signaling overrides p53-mediated tumor suppression by activating Mdm2 , 2008, Proceedings of the National Academy of Sciences.

[125]  Joel I. Pritchard,et al.  The Smo/Smo model: hedgehog-induced medulloblastoma with 90% incidence and leptomeningeal spread. , 2008, Cancer research.

[126]  Jiri Bartek,et al.  An Oncogene-Induced DNA Damage Model for Cancer Development , 2008, Science.

[127]  Jean Gautier,et al.  A forward chemical genetic screen reveals an inhibitor of the Mre11-Rad50-Nbs1 complex. , 2008, Nature chemical biology.

[128]  K. Fukasawa.  Oncogenes and tumour suppressors take on centrosomes , 2007, Nature Reviews Cancer.

[129]  J. Bartek,et al.  DNA Damage Response as an Anti-Cancer Barrier: Damage Threshold and the Concept of 'Conditional Haploinsufficiency' , 2007, Cell cycle.

[130]  P. Mckinnon,et al.  BRCA2 is required for neurogenesis and suppression of medulloblastoma , 2007, The EMBO journal.

[131]  L. Skoog,et al.  Intact Mre11/Rad50/Nbs1 complex predicts good response to radiotherapy in early breast cancer. , 2007, International journal of radiation oncology, biology, physics.

[132]  S. Chiou,et al.  Overexpression of NBS1 induces epithelial–mesenchymal transition and co-expression of NBS1 and Snail predicts metastasis of head and neck cancer , 2007, Oncogene.

[133]  C. Lilley,et al.  Using or abusing: viruses and the cellular DNA damage response. , 2007, Trends in microbiology.

[134]  H. Vogel,et al.  Ku80 and p53 suppress medulloblastoma that arise independent of Rag-1-induced DSBs , 2006, Oncogene.

[135]  Aaron Bensimon,et al.  Oncogene-induced senescence is a DNA damage response triggered by DNA hyper-replication , 2006, Nature.

[136]  Dimitris Kletsas,et al.  Oncogene-induced senescence is part of the tumorigenesis barrier imposed by DNA damage checkpoints , 2006, Nature.

[137]  W. Ewens,et al.  Heterozygous carriers of Nijmegen Breakage Syndrome have a distinct gene expression phenotype. , 2006, Genome research.

[138]  Michael M. Murphy,et al.  XRCC4 suppresses medulloblastomas with recurrent translocations in p53-deficient mice. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[139]  V. Costanzo,et al.  ATM and ATR promote Mre11 dependent restart of collapsed replication forks and prevent accumulation of DNA breaks , 2006, The EMBO journal.

[140]  J. Shay,et al.  The involvement of the Mre11/Rad50/Nbs1 complex in the generation of G‐overhangs at human telomeres , 2006, EMBO reports.

[141]  T. Chou,et al.  Increased NBS1 Expression Is a Marker of Aggressive Head and Neck Cancer and Overexpression of NBS1 Contributes to Transformation , 2006, Clinical Cancer Research.

[142]  Hiroyuki Shimada,et al.  Chromosome 1p and 11q deletions and outcome in neuroblastoma. , 2005, The New England journal of medicine.

[143]  M. Weitzman,et al.  Adenovirus Type 5 E4orf3 Protein Targets the Mre11 Complex to Cytoplasmic Aggresomes , 2005, Journal of Virology.

[144]  K. Manova,et al.  Role of Nbs1 in the activation of the Atm kinase revealed in humanized mouse models , 2005, Nature Cell Biology.

[145]  M. Weitzman,et al.  Serotype-Specific Reorganization of the Mre11 Complex by Adenoviral E4orf3 Proteins , 2005, Journal of Virology.

[146]  Z. Herceg,et al.  An essential function for NBS1 in the prevention of ataxia and cerebellar defects , 2005, Nature Medicine.

[147]  C. Lilley,et al.  DNA repair proteins affect the lifecycle of herpes simplex virus 1. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[148]  T. Ørntoft,et al.  DNA damage response as a candidate anti-cancer barrier in early human tumorigenesis , 2005, Nature.

[149]  Justis P. Ehlers,et al.  NBS1 Expression as a Prognostic Marker in Uveal Melanoma , 2005, Clinical Cancer Research.

[150]  Andreas Radbruch,et al.  Nibrin functions in Ig class-switch recombination. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[151]  D. Delia,et al.  MRE11 mutations and impaired ATM-dependent responses in an Italian family with ataxia-telangiectasia-like disorder. , 2004, Human molecular genetics.

[152]  K. Cerosaletti,et al.  Independent Roles for Nibrin and Mre11-Rad50 in the Activation and Function of Atm* , 2004, Journal of Biological Chemistry.

[153]  Karl Sperling,et al.  Increased cancer risk of heterozygotes with NBS1 germline mutations in poland , 2004, International journal of cancer.

[154]  S. Jackson,et al.  Functional links between telomeres and proteins of the DNA-damage response. , 2004, Genes & development.

[155]  S. Weller,et al.  Recruitment of Cellular Recombination and Repair Proteins to Sites of Herpes Simplex Virus Type 1 DNA Replication Is Dependent on the Composition of Viral Proteins within Prereplicative Sites and Correlates with the Induction of the DNA Damage Response , 2004, Journal of Virology.

[156]  Z. Herceg,et al.  Nbn heterozygosity renders mice susceptible to tumor formation and ionizing radiation-induced tumorigenesis. , 2003, Cancer research.

[157]  Yair Andegeko,et al.  Requirement of the MRN complex for ATM activation by DNA damage , 2003, The EMBO journal.

[158]  J. Carney,et al.  Mutant Nbs1 Enhances Cisplatin-Induced DNA Damage and Cytotoxicity in Head and Neck Cancer , 2003, Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery.

[159]  Kou-Juey Wu,et al.  c-Myc Directly Regulates the Transcription of the NBS1 Gene Involved in DNA Double-strand Break Repair * , 2003, Journal of Biological Chemistry.

[160]  K. Cerosaletti,et al.  Medulloblastoma with adverse reaction to radiation therapy in nijmegen breakage syndrome. , 2003, Journal of pediatric hematology/oncology.

[161]  M. Weitzman,et al.  Adenovirus oncoproteins inactivate the Mre11–Rad50–NBS1 DNA repair complex , 2002, Nature.

[162]  K. Chrzanowska,et al.  Alternative end joining during switch recombination in patients with Ataxia‐Telangiectasia , 2002, European journal of immunology.

[163]  William F. Morgan,et al.  A Murine Model of Nijmegen Breakage Syndrome , 2002, Current Biology.

[164]  Thomas Ried,et al.  AID is required to initiate Nbs1/γ-H2AX focus formation and mutations at sites of class switching , 2001, Nature.

[165]  R. Wegner,et al.  High frequency of spontaneous translocations revealed by FISH in cells from patients with the cancer-prone syndromes ataxia telangiectasia and Nijmegen breakage syndrome , 2001, Cytogenetic and Genome Research.

[166]  R. S. Maser,et al.  An alternative mode of translation permits production of a variant NBS1 protein from the common Nijmegen breakage syndrome allele , 2001, Nature Genetics.

[167]  Lino Tessarollo,et al.  Targeted disruption of the Nijmegen breakage syndrome gene NBS1 leads to early embryonic lethality in mice , 2001, Current Biology.

[168]  T. Stankovic,et al.  The DNA Double-Strand Break Repair Gene hMRE11 Is Mutated in Individuals with an Ataxia-Telangiectasia-like Disorder , 1999, Cell.

[169]  T Yagi,et al.  Mre11 is essential for the maintenance of chromosomal DNA in vertebrate cells , 1999, The EMBO journal.

[170]  D. Stram,et al.  Allelic deletion at 11q23 is common in MYCN single copy neuroblastomas , 1999, Oncogene.

[171]  A. Bradley,et al.  Disruption of mRad50 causes embryonic stem cell lethality, abnormal embryonic development, and sensitivity to ionizing radiation. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[172]  D. Weaver,et al.  Conditional gene targeted deletion by Cre recombinase demonstrates the requirement for the double-strand break repair Mre11 protein in murine embryonic stem cells. , 1997, Nucleic acids research.

[173]  H. Seyschab,et al.  Chromosome instability and X-ray hypersensitivity in a microcephalic and growth-retarded child. , 1991, American journal of medical genetics.

[174]  E. Seemanová.  An increased risk for malignant neoplasms in heterozygotes for a syndrome of microcephaly, normal intelligence, growth retardation, remarkable facies, immunodeficiency and chromosomal instability. , 1990, Mutation research.

[175]  OUP accepted manuscript , 2022, Nucleic Acids Research.

[176]  H. Xiong,et al.  Targeting RAD50 increases sensitivity to radiotherapy in colorectal cancer cells. , 2018, Neoplasma.

[177]  Gerald Li,et al.  Integrated tumor identification and automated scoring minimizes pathologist involvement and provides new insights to key biomarkers in breast cancer , 2018, Laboratory Investigation.

[178]  F. Roviello,et al.  KRAS Mutation in Gastric Cancer and Prognostication Associated with Microsatellite Instability Status , 2017, Pathology & Oncology Research.

[179]  I. Demuth,et al.  Cancer incidence in Nijmegen breakage syndrome is modulated by the amount of a variant NBS protein. , 2007, Carcinogenesis.

[180]  P. Kleihues,et al.  Null mutation of DNA strand break-binding molecule poly(ADP-ribose) polymerase causes medulloblastomas in p53(-/-) mice. , 2003, The American journal of pathology.

[181]  W. Marshall,et al.  Are there nucleic acids in the centrosome? , 2000, Current topics in developmental biology.

[182]  W. Xiao,et al.  Formation of the yeast Mre11-Rad50-Xrs2 complex is correlated with DNA repair and telomere maintenance. , 1999, Nucleic acids research.