{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T18:11:26Z","timestamp":1792087886352,"version":"4.4.0"},"reference-count":148,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2015,10,23]],"date-time":"2015-10-23T00:00:00Z","timestamp":1445558400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>The recognition, signalling and repair of DNA double strand breaks (DSB) involves the participation of a multitude of proteins and post-translational events that ensure maintenance of genome integrity. Amongst the proteins involved are several which when mutated give rise to genetic disorders characterised by chromosomal abnormalities, cancer predisposition, neurodegeneration and other pathologies. ATM (mutated in ataxia-telangiectasia (A-T) and members of the Mre11\/Rad50\/Nbs1 (MRN complex) play key roles in this process. The MRN complex rapidly recognises and locates to DNA DSB where it acts to recruit and assist in ATM activation. ATM, in the company of several other DNA damage response proteins, in turn phosphorylates all three members of the MRN complex to initiate downstream signalling. While ATM has hundreds of substrates, members of the MRN complex play a pivotal role in mediating the downstream signalling events that give rise to cell cycle control, DNA repair and ultimately cell survival or apoptosis. Here we focus on the interplay between ATM and the MRN complex in initiating signaling of breaks and more specifically on the adaptor role of the MRN complex in mediating ATM signalling to downstream substrates to control different cellular processes.<\/jats:p>","DOI":"10.3390\/biom5042877","type":"journal-article","created":{"date-parts":[[2015,10,24]],"date-time":"2015-10-24T08:27:06Z","timestamp":1445675226000},"page":"2877-2902","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":140,"title":["ATM-Dependent Phosphorylation of All Three Members of the MRN Complex: From Sensor to Adaptor"],"prefix":"10.3390","volume":"5","author":[{"given":"Martin","family":"Lavin","sequence":"first","affiliation":[{"name":"UQ Centre for Clinical Research, The University of Queensland, Brisbane, QLD 4029, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sergei","family":"Kozlov","sequence":"additional","affiliation":[{"name":"UQ Centre for Clinical Research, The University of Queensland, Brisbane, QLD 4029, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Magtouf","family":"Gatei","sequence":"additional","affiliation":[{"name":"UQ Centre for Clinical Research, The University of Queensland, Brisbane, QLD 4029, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amanda","family":"Kijas","sequence":"additional","affiliation":[{"name":"UQ Centre for Clinical Research, The University of Queensland, Brisbane, QLD 4029, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2015,10,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1016\/j.dnarep.2015.04.021","article-title":"Accessing DNA damage in chromatin: Preparing the chromatin landscape for base excision repair","volume":"32","author":"Rodriguez","year":"2015","journal-title":"DNA Repair"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"426","DOI":"10.1016\/j.tcb.2014.01.005","article-title":"Crosstalk between ubiquitin and other post-translational modifications on chromatin during double-strand break repair","volume":"24","author":"Zhao","year":"2014","journal-title":"Trends Cell Biol."},{"key":"ref_3","first-page":"3857","article-title":"Interaction between ionizing radiation and supercoiled DNA within human tumor cells","volume":"51","author":"Vaughan","year":"1991","journal-title":"Cancer Res."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1240","DOI":"10.1126\/science.1177321","article-title":"Poly(ADP-ribose)-dependent regulation of DNA repair by the chromatin remodeling enzyme ALC1","volume":"325","author":"Ahel","year":"2009","journal-title":"Science"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"13770","DOI":"10.1073\/pnas.0906920106","article-title":"Poly(ADP-ribosyl)ation directs recruitment and activation of an ATP-dependent chromatin remodeler","volume":"106","author":"Gottschalk","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"731","DOI":"10.1083\/jcb.200912135","article-title":"The chromatin-remodeling factor CHD4 coordinates signaling and repair after DNA damage","volume":"190","author":"Larsen","year":"2010","journal-title":"J. Cell Biol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1161","DOI":"10.1038\/ncb2344","article-title":"More than just a focus: The chromatin response to DNA damage and its role in genome integrity maintenance","volume":"13","author":"Lukas","year":"2011","journal-title":"Nat. Cell Biol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"723","DOI":"10.1016\/j.molcel.2014.06.028","article-title":"Requirement for PBAF in transcriptional repression and repair at DNA breaks in actively transcribed regions of chromatin","volume":"55","author":"Kakarougkas","year":"2014","journal-title":"Mol. Cell"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"970","DOI":"10.1016\/j.cell.2010.04.038","article-title":"ATM-dependent chromatin changes silence transcription in cis to DNA double-strand breaks","volume":"141","author":"Shanbhag","year":"2010","journal-title":"Cell"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"5858","DOI":"10.1074\/jbc.273.10.5858","article-title":"DNA double-stranded breaks induce histone H2AX phosphorylation on serine 139","volume":"273","author":"Rogakou","year":"1998","journal-title":"J. Biol. Chem."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"675","DOI":"10.1038\/ncb1004","article-title":"Histone H2AX phosphorylation is dispensable for the initial recognition of DNA breaks","volume":"5","author":"Celeste","year":"2003","journal-title":"Nat. Cell Biol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"591","DOI":"10.1038\/nature07849","article-title":"Tyrosine dephosphorylation of H2AX modulates apoptosis and survival decisions","volume":"458","author":"Cook","year":"2009","journal-title":"Nature"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1038\/nature07668","article-title":"Wstf regulates the H2AX DNA damage response via a novel tyrosine kinase activity","volume":"457","author":"Xiao","year":"2009","journal-title":"Nature"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1101\/gad.2021311","article-title":"Dynamics of DNA damage response proteins at DNA breaks: A focus on protein modifications","volume":"25","author":"Polo","year":"2011","journal-title":"Genes Dev."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1016\/j.yexcr.2014.09.002","article-title":"ATM: Expanding roles as a chief guardian of genome stability","volume":"329","author":"Shiloh","year":"2014","journal-title":"Exp. Cell. Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1016\/j.molcel.2009.04.012","article-title":"Formation of dynamic gamma-H2AX domains along broken DNA strands is distinctly regulated by ATM and MDC1 and dependent upon H2AX densities in chromatin","volume":"34","author":"Savic","year":"2009","journal-title":"Mol. Cell"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"930","DOI":"10.4161\/cc.9.5.10931","article-title":"Tip60: Connecting chromatin to DNA damage signaling","volume":"9","author":"Sun","year":"2010","journal-title":"Cell Cycle"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"9169","DOI":"10.1073\/pnas.1403565111","article-title":"DNA double-strand breaks promote methylation of histone H3 on lysine 9 and transient formation of repressive chromatin","volume":"111","author":"Ayrapetov","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"406","DOI":"10.1038\/nature03114","article-title":"Methylated lysine 79 of histone H3 targets 53BP1 to DNA double-strand breaks","volume":"432","author":"Huyen","year":"2004","journal-title":"Nature"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1038\/nature09658","article-title":"Mmset regulates histone H4K20 methylation and 53BP1 accumulation at DNA damage sites","volume":"470","author":"Pei","year":"2011","journal-title":"Nature"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2914","DOI":"10.1016\/j.febslet.2011.05.056","article-title":"The ubiquitin- and sumo-dependent signaling response to DNA double-strand breaks","volume":"585","author":"Mailand","year":"2011","journal-title":"FEBS Lett."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"887","DOI":"10.1016\/j.cell.2007.09.040","article-title":"RNF8 ubiquitylates histones at DNA double-strand breaks and promotes assembly of repair proteins","volume":"131","author":"Mailand","year":"2007","journal-title":"Cell"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Brown, J.S., and Jackson, S.P. (2015). Ubiquitylation, neddylation and the DNA damage response. Open Biol.","DOI":"10.1098\/rsob.150018"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1273","DOI":"10.1016\/j.dnarep.2010.09.013","article-title":"The influence of heterochromatin on DNA double strand break repair: Getting the strong, silent type to relax","volume":"9","author":"Goodarzi","year":"2010","journal-title":"DNA Repair"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Cejka, P. (2015). DNA end resection: Nucleases team up with the right partners to initiate homologous recombination. J. Biol. Chem.","DOI":"10.1074\/jbc.R115.675942"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"7720","DOI":"10.1073\/pnas.1213431110","article-title":"Microhomology-mediated end joining and homologous recombination share the initial end resection step to repair DNA double-strand breaks in mammalian cells","volume":"110","author":"Truong","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"12706","DOI":"10.1021\/bi0263558","article-title":"The DNA-dependent protein kinase interacts with DNA to form a protein-DNA complex that is disrupted by phosphorylation","volume":"41","author":"Merkle","year":"2002","journal-title":"Biochemistry"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1126\/science.1261971","article-title":"PAXX, a paralog of XRCC4 and Xlf, interacts with Ku to promote DNA double-strand break repair","volume":"347","author":"Ochi","year":"2015","journal-title":"Science"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"37112","DOI":"10.1074\/jbc.M113.514398","article-title":"DNA-dependent protein kinase regulates DNA end resection in concert with mre11-rad50-nbs1 (MRN) and ataxia telangiectasia-mutated (ATM)","volume":"288","author":"Zhou","year":"2013","journal-title":"J. Biol. Chem."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"3643","DOI":"10.1093\/nar\/gkq1340","article-title":"hSSB1 interacts directly with the mrn complex stimulating its recruitment to DNA double-strand breaks and its endo-nuclease activity","volume":"39","author":"Richard","year":"2011","journal-title":"Nucleic Acids Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1038\/embor.2012.58","article-title":"CDK targeting of nbs1 promotes DNA-end resection, replication restart and homologous recombination","volume":"13","author":"Falck","year":"2012","journal-title":"EMBO Rep."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1080\/19491034.2015.1010946","article-title":"DNA double strand break repair pathway choice: A chromatin based decision?","volume":"6","author":"Clouaire","year":"2015","journal-title":"Nucleus"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Sarangi, P., Steinacher, R., Altmannova, V., Fu, Q., Paull, T.T., Krejci, L., Whitby, M.C., and Zhao, X. (2015). Sumoylation influences DNA break repair partly by increasing the solubility of a conserved end resection protein. PLoS Genet.","DOI":"10.1371\/journal.pgen.1004899"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1016\/j.celrep.2014.05.044","article-title":"Mof phosphorylation by ATM regulates 53BP1-mediated double-strand break repair pathway choice","volume":"8","author":"Gupta","year":"2014","journal-title":"Cell Rep."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"872","DOI":"10.1016\/j.molcel.2013.01.001","article-title":"A cell cycle-dependent regulatory circuit composed of 53BP1-RIF1 and BRCA1-CtIP controls DNA repair pathway choice","volume":"49","author":"Orthwein","year":"2013","journal-title":"Mol. cell"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1038\/nrm805","article-title":"The Mre11 complex: At the crossroads of DNA repair and checkpoint signalling","volume":"3","author":"Jackson","year":"2002","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"844","DOI":"10.1038\/sj.embor.embor925","article-title":"The mrn complex: Coordinating and mediating the response to broken chromosomes","volume":"4","author":"Bree","year":"2003","journal-title":"EMBO Rep."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"605","DOI":"10.1016\/j.ajhg.2009.04.010","article-title":"Human RAD50 deficiency in a nijmegen breakage syndrome-like disorder","volume":"84","author":"Waltes","year":"2009","journal-title":"Am. J. Hum. Genet."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1016\/S0092-8674(00)81547-0","article-title":"The DNA double-strand break repair gene hMRE11 is mutated in individuals with an ataxia-telangiectasia-like disorder","volume":"99","author":"Stewart","year":"1999","journal-title":"Cell"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1016\/S0092-8674(00)81175-7","article-title":"The hMRE11\/hRAD50 protein complex and Nijmegen breakage syndrome: Linkage of double-strand break repair to the cellular DNA damage response","volume":"93","author":"Carney","year":"1998","journal-title":"Cell"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1016\/j.molcel.2014.12.018","article-title":"Interdependence of the RAD50 hook and globular domain functions","volume":"57","author":"Hohl","year":"2015","journal-title":"Mol. Cell"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1016\/j.pbiomolbio.2014.12.004","article-title":"Envisioning the dynamics and flexibility of MRE11-RAD50-NBS1 complex to decipher its roles in DNA replication and repair","volume":"117","author":"Williams","year":"2015","journal-title":"Prog. Biophys. Mol. Biol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"482","DOI":"10.1002\/embj.201386100","article-title":"ATP-driven RAD50 conformations regulate DNA tethering, end resection, and ATM checkpoint signaling","volume":"33","author":"Deshpande","year":"2014","journal-title":"EMBO J."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1016\/j.cell.2008.08.015","article-title":"MRE11 nuclease activity has essential roles in DNA repair and genomic stability distinct from ATM activation","volume":"135","author":"Buis","year":"2008","journal-title":"Cell"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"12840","DOI":"10.1074\/jbc.M113.460378","article-title":"Ataxia telangiectasia-mutated (ATM) kinase activity is regulated by ATP-driven conformational changes in the MRE11\/RAD50\/NBS1 (MRN) complex","volume":"288","author":"Lee","year":"2013","journal-title":"J. Biol. Chem."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"711","DOI":"10.1146\/annurev-biochem-060614-034335","article-title":"Mechanisms of ATM activation","volume":"84","author":"Paull","year":"2015","journal-title":"Annu. Rev. Biochem."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"759","DOI":"10.1038\/nrm2514","article-title":"Ataxia-telangiectasia: From a rare disorder to a paradigm for cell signalling and cancer","volume":"9","author":"Lavin","year":"2008","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1128\/MCB.21.1.281-288.2001","article-title":"DNA damage-dependent nuclear dynamics of the MRE11 complex","volume":"21","author":"Mirzoeva","year":"2001","journal-title":"Mol. Cell. Biol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"5612","DOI":"10.1093\/emboj\/cdg541","article-title":"Requirement of the MRN complex for ATM activation by DNA damage","volume":"22","author":"Uziel","year":"2003","journal-title":"EMBO J."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"6610","DOI":"10.1093\/emboj\/cdg630","article-title":"The MRE11 complex is required for ATM activation and the G2\/M checkpoint","volume":"22","author":"Carson","year":"2003","journal-title":"EMBO J."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"34277","DOI":"10.1074\/jbc.274.48.34277","article-title":"Localization of a portion of extranuclear ATM to peroxisomes","volume":"274","author":"Watters","year":"1999","journal-title":"J. Biol. Chem."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"840","DOI":"10.4161\/auto.19693","article-title":"A new role for ATM: Regulating mitochondrial function and mitophagy","volume":"8","author":"Kastan","year":"2012","journal-title":"Autophagy"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1038\/nature01368","article-title":"DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation","volume":"421","author":"Bakkenist","year":"2003","journal-title":"Nature"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"3504","DOI":"10.1038\/sj.emboj.7601231","article-title":"Involvement of novel autophosphorylation sites in ATM activation","volume":"25","author":"Kozlov","year":"2006","journal-title":"EMBO J."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"9107","DOI":"10.1074\/jbc.M110.204065","article-title":"Autophosphorylation and ATM activation: Additional sites add to the complexity","volume":"286","author":"Kozlov","year":"2011","journal-title":"J. Biol. Chem."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1038\/nature05112","article-title":"Autophosphorylation at serine 1987 is dispensable for murine ATM activation in vivo","volume":"443","author":"Pellegrini","year":"2006","journal-title":"Nature"},{"key":"ref_57","first-page":"777","article-title":"Multiple autophosphorylation sites are dispensable for murine ATM activation in vivo","volume":"183","author":"Daniel","year":"2008","journal-title":"J. Biol. Chem."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1038\/nsmb1090","article-title":"Two-step activation of ATM by DNA and the MRE11-RAD50-NBS1 complex","volume":"13","author":"Dupre","year":"2006","journal-title":"Nat. Struct. Mol. Biol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"7741","DOI":"10.1038\/sj.onc.1210872","article-title":"Activation and regulation of ATM kinase activity in response to DNA double-strand breaks","volume":"26","author":"Lee","year":"2007","journal-title":"Oncogene"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"8502","DOI":"10.1128\/MCB.01382-07","article-title":"DNA damage-induced acetylation of lysine 3016 of ATM activates ATM kinase activity","volume":"27","author":"Sun","year":"2007","journal-title":"Mol. Cell. Biol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1038\/nature12201","article-title":"KAT5 tyrosine phosphorylation couples chromatin sensing to ATM signalling","volume":"498","author":"Kaidi","year":"2013","journal-title":"Nature"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"761","DOI":"10.1038\/nsmb.2078","article-title":"Chfr and RNF8 synergistically regulate ATM activation","volume":"18","author":"Wu","year":"2011","journal-title":"Nat. Struct. Mol. Biol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1038\/nature14512","article-title":"The core spliceosome as target and effector of non-canonical ATM signalling","volume":"523","author":"Tresini","year":"2015","journal-title":"Nature"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"4036","DOI":"10.1182\/blood-2012-09-456897","article-title":"Pathogenesis of ataxia-telangiectasia: The next generation of ATM functions","volume":"121","author":"Ambrose","year":"2013","journal-title":"Blood"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1028","DOI":"10.1016\/j.dnarep.2008.03.006","article-title":"The neurological phenotype of ataxia-telangiectasia: Solving a persistent puzzle","volume":"7","author":"Biton","year":"2008","journal-title":"DNA Repair"},{"key":"ref_66","doi-asserted-by":"crossref","unstructured":"Lavin, M.F., Gueven, N., Bottle, S., and Gatti, R.A. (2007). Current and potential therapeutic strategies for the treatment of ataxia-telangiectasia. Br. Med. Bull.","DOI":"10.1093\/bmb\/ldm012"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"2025","DOI":"10.1093\/hmg\/4.11.2025","article-title":"The complete sequence of the coding region of the ATM gene reveals similarity to cell cycle regulators in different species","volume":"4","author":"Savitsky","year":"1995","journal-title":"Hum. Mol. Genet."},{"key":"ref_68","first-page":"911","article-title":"Hypothesis: Ataxia-telangiectasia: Is ATM a sensor of oxidative damage and stress?","volume":"19","author":"Rotman","year":"1997","journal-title":"Cell Mol. Biol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"564","DOI":"10.1111\/j.1468-1331.2010.03203.x","article-title":"Efficacy of very-low-dose betamethasone on neurological symptoms in ataxia-telangiectasia","volume":"18","author":"Broccoletti","year":"2011","journal-title":"Eur. J. Neurol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1111\/j.1468-1331.2008.02060.x","article-title":"Steroid-induced improvement of neurological signs in ataxia-telangiectasia patients","volume":"15","author":"Broccoletti","year":"2008","journal-title":"Eur. J. Neurol."},{"key":"ref_71","doi-asserted-by":"crossref","unstructured":"Chessa, L., Leuzzi, V., Plebani, A., Soresina, A., Micheli, R., D\u2019Agnano, D., Venturi, T., Molinaro, A., Fazzi, E., and Marini, M. (2014). Intra-erythrocyte infusion of dexamethasone reduces neurological symptoms in ataxia teleangiectasia patients: Results of a phase 2 trial. Orphanet J. Rare Dis.","DOI":"10.1186\/1750-1172-9-5"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1016\/j.ejpn.2012.06.002","article-title":"Steroid treatment in ataxia-telangiectasia induces alterations of functional magnetic resonance imaging during prono-supination task","volume":"17","author":"Quarantelli","year":"2013","journal-title":"Eur. J. Paediatr. Neurol."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"847","DOI":"10.1002\/ppul.21277","article-title":"Evaluation and management of pulmonary disease in ataxia-telangiectasia","volume":"45","author":"Gower","year":"2010","journal-title":"Pediatr. Pulm."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/S1568-7864(01)00007-6","article-title":"ATM deficiency and oxidative stress: A new dimension of defective response to DNA damage","volume":"1","author":"Barzilai","year":"2002","journal-title":"DNA Repair"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"332","DOI":"10.1016\/j.immuni.2015.01.012","article-title":"DNA damage primes the type I interferon system via the cytosolic DNA sensor sting to promote anti-microbial innate immunity","volume":"42","author":"Hartlova","year":"2015","journal-title":"Immunity"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"785","DOI":"10.1016\/j.celrep.2015.03.069","article-title":"DNA-damage-induced type I interferon promotes senescence and inhibits stem cell function","volume":"11","author":"Yu","year":"2015","journal-title":"Cell Rep."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"9915","DOI":"10.1073\/pnas.96.17.9915","article-title":"Loss of the ataxia-telangiectasia gene product causes oxidative damage in target organs","volume":"96","author":"Barlow","year":"1999","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"11453","DOI":"10.1523\/JNEUROSCI.23-36-11453.2003","article-title":"Oxidative stress is responsible for deficient survival and dendritogenesis in purkinje neurons from ataxia-telangiectasia mutated mutant mice","volume":"23","author":"Chen","year":"2003","journal-title":"J. Neurosci."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"992","DOI":"10.1016\/j.freeradbiomed.2006.06.018","article-title":"Dramatic extension of tumor latency and correction of neurobehavioral phenotype in ATM-mutant mice with a nitroxide antioxidant","volume":"41","author":"Gueven","year":"2006","journal-title":"Free Radical Biol. Med."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"1793","DOI":"10.1093\/hmg\/ddh189","article-title":"Cancer chemoprevention by the antioxidant tempol in ATM-deficient mice","volume":"13","author":"Schubert","year":"2004","journal-title":"Hum. Mol. Genet."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"S229","DOI":"10.1093\/jn\/137.1.229S","article-title":"Antioxidants suppress lymphoma and increase longevity in ATM-deficient mice","volume":"137","author":"Reliene","year":"2007","journal-title":"J. Nutr."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1016\/j.bbrc.2012.01.008","article-title":"Activation of amp-activated protein kinase in cerebella of ATM\u2212\/\u2212 mice is attributable to accumulation of reactive oxygen species","volume":"418","author":"Kuang","year":"2012","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"627","DOI":"10.1002\/ana.1005","article-title":"Superoxide stress identifies neurons at risk in a model of ataxia-telangiectasia","volume":"49","author":"Quick","year":"2001","journal-title":"Ann. Neurol."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"3997","DOI":"10.1073\/pnas.1416031112","article-title":"ATM prevents dsb formation by coordinating ssb repair and cell cycle progression","volume":"112","author":"Khoronenkova","year":"2015","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"21951","DOI":"10.1074\/jbc.M011303200","article-title":"The ataxia telangiectasia gene product is required for oxidative stress-induced G1 and G2 checkpoint function in human fibroblasts","volume":"276","author":"Shackelford","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"4805","DOI":"10.4161\/cc.9.24.14323","article-title":"ATM activation in the presence of oxidative stress","volume":"9","author":"Guo","year":"2010","journal-title":"Cell cycle"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"25402","DOI":"10.1074\/jbc.M109.097162","article-title":"Redox regulation of transglutaminase 2 activity","volume":"285","author":"Stamnaes","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"747","DOI":"10.1016\/j.molcel.2012.10.007","article-title":"Loss of the oxidative stress sensor NPGPx compromises GRP78 chaperone activity and induces systemic disease","volume":"48","author":"Wei","year":"2012","journal-title":"Mol. Cell"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1126\/science.1192912","article-title":"ATM activation by oxidative stress","volume":"330","author":"Guo","year":"2010","journal-title":"Science"},{"key":"ref_90","doi-asserted-by":"crossref","unstructured":"Lee, J.H., Guo, Z., Myler, L.R., Zheng, S., and Paull, T.T. (2014). Direct activation of ATM by resveratrol under oxidizing conditions. PLoS ONE.","DOI":"10.1371\/journal.pone.0097969"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"27587","DOI":"10.1074\/jbc.M411689200","article-title":"Identification of domains of ataxia-telangiectasia mutated required for nuclear localization and chromatin association","volume":"280","author":"Young","year":"2005","journal-title":"J. Biol. Chem."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"526","DOI":"10.1128\/MCB.01301-08","article-title":"ATM activation and signaling under hypoxic conditions","volume":"29","author":"Bencokova","year":"2009","journal-title":"Mol. Cell. Biol."},{"key":"ref_93","doi-asserted-by":"crossref","unstructured":"Zhang, J., Tripathi, D.N., Jing, J., Alexander, A., Kim, J., Powell, R.T., Dere, R., Tait-Mulder, J., Lee, J.H., and Paull, T.T. (2015). ATM functions at the peroxisome to induce pexophagy in response to ROS. Nat. Cell Biol.","DOI":"10.1038\/ncb3230"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"1160","DOI":"10.1126\/science.1140321","article-title":"ATM and ATR substrate analysis reveals extensive protein networks responsive to DNA damage","volume":"316","author":"Matsuoka","year":"2007","journal-title":"Science"},{"key":"ref_95","doi-asserted-by":"crossref","unstructured":"Bensimon, A., Schmidt, A., Ziv, Y., Elkon, R., Wang, S.Y., Chen, D.J., Aebersold, R., and Shiloh, Y. (2010). ATM-dependent and -independent dynamics of the nuclear phosphoproteome after DNA damage. Sci. Signal.","DOI":"10.1126\/scisignal.2001034"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"212","DOI":"10.1016\/j.molcel.2012.01.026","article-title":"Proteomic investigations reveal a role for RNA processing factor THRAP3 in the DNA damage response","volume":"46","author":"Beli","year":"2012","journal-title":"Mol. Cell"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"2091","DOI":"10.1016\/j.cub.2009.10.039","article-title":"Cytoplasmic ATM in neurons modulates synaptic function","volume":"19","author":"Li","year":"2009","journal-title":"Curr. Biol."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1016\/j.bbrc.2010.11.135","article-title":"ATM-mediated nusap phosphorylation induces mitotic arrest","volume":"404","author":"Xie","year":"2011","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"1625","DOI":"10.1016\/j.febslet.2011.05.013","article-title":"Beyond ATM: The protein kinase landscape of the DNA damage response","volume":"585","author":"Bensimon","year":"2011","journal-title":"FEBS Lett."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"194","DOI":"10.1016\/j.pbiomolbio.2014.12.003","article-title":"The DNA-dependent protein kinase: A multifunctional protein kinase with roles in DNA double strand break repair and mitosis","volume":"117","author":"Jette","year":"2015","journal-title":"Prog. Biophys. Mol. Biol."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1016\/j.dnarep.2014.02.020","article-title":"DNA-PK: A dynamic enzyme in a versatile DSB repair pathway","volume":"17","author":"Davis","year":"2014","journal-title":"DNA Repair"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1038\/ncb2897","article-title":"Causes and consequences of replication stress","volume":"16","author":"Zeman","year":"2014","journal-title":"Nat. Cell Biol."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1111\/gtc.12033","article-title":"Role of SMG-1-mediated Upf1 phosphorylation in mammalian nonsense-mediated mRNA decay","volume":"18","author":"Yamashita","year":"2013","journal-title":"Genes cells"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"4417","DOI":"10.1128\/MCB.05987-11","article-title":"A novel role for hSMG-1 in stress granule formation","volume":"31","author":"Brown","year":"2011","journal-title":"Mol. Cell. Biol."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"E285","DOI":"10.1073\/pnas.1215696110","article-title":"SMG1 haploinsufficiency predisposes to tumor formation and inflammation","volume":"110","author":"Roberts","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_106","doi-asserted-by":"crossref","unstructured":"Showkat, M., Beigh, M.A., and Andrabi, K.I. (2014). mTOR signaling in protein translation regulation: Implications in cancer genesis and therapeutic interventions. Biochem. Mol. Biol. Int.","DOI":"10.1155\/2014\/686984"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"605","DOI":"10.1038\/nature03442","article-title":"Conserved modes of recruitment of ATM, ATR and DNA-PKcs to sites of DNA damage","volume":"434","author":"Falck","year":"2005","journal-title":"Nature"},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"5363","DOI":"10.1128\/MCB.25.13.5363-5379.2005","article-title":"ATM activation and its recruitment to damaged DNA require binding to the C terminus of nbs1","volume":"25","author":"You","year":"2005","journal-title":"Mol. Cell. Biol."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"931","DOI":"10.4161\/cc.6.8.4180","article-title":"ATM activation and DNA damage response","volume":"6","author":"Lavin","year":"2007","journal-title":"Cell Cycle"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1038\/35013083","article-title":"Functional link between ataxia-telangiectasia and Nijmegen breakage syndrome gene products","volume":"405","author":"Zhao","year":"2000","journal-title":"Nature"},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1038\/35007091","article-title":"ATM phosphorylates p95\/nbs1 in an S-phase checkpoint pathway","volume":"404","author":"Lim","year":"2000","journal-title":"Nature"},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1038\/35013089","article-title":"ATM phosphorylation of Nijmegen breakage syndrome protein is required in a DNA damage response","volume":"405","author":"Wu","year":"2000","journal-title":"Nature"},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1038\/75508","article-title":"ATM-dependent phosphorylation of nibrin in response to radiation exposure","volume":"25","author":"Gatei","year":"2000","journal-title":"Nat. Genet."},{"key":"ref_114","first-page":"674","article-title":"Distinct functions of nijmegen breakage syndrome in ataxia telangiectasia mutated-dependent responses to DNA damage","volume":"1","author":"Lee","year":"2003","journal-title":"Mol. Cancer Res."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"382","DOI":"10.1016\/j.mad.2011.05.001","article-title":"Point mutation at the Nbs1 threonine 278 site does not affect mouse development, but compromises the Chk2 and SMC1 phosphorylation after DNA damage","volume":"132","author":"Li","year":"2011","journal-title":"Mech. Ageing Dev."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"1893","DOI":"10.1126\/science.282.5395.1893","article-title":"Linkage of ATM to cell cycle regulation by the Chk2 protein kinase","volume":"282","author":"Matsuoka","year":"1998","journal-title":"Science"},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"5214","DOI":"10.1128\/MCB.21.15.5214-5222.2001","article-title":"Chk2 activation dependence on Nbs1 after DNA damage","volume":"21","author":"Buscemi","year":"2001","journal-title":"Mol. Cell. Biol."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"571","DOI":"10.1101\/gad.970702","article-title":"SMC1 is a downstream effector in the ATM\/Nbs1 branch of the human S-phase checkpoint","volume":"16","author":"Yazdi","year":"2002","journal-title":"Genes Dev."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"19176","DOI":"10.1074\/jbc.M802299200","article-title":"Regulation of intra-S phase checkpoint by Ionizing Radiation (IR)-dependent and IR-independent phosphorylation of SMC3","volume":"283","author":"Luo","year":"2008","journal-title":"J. Biol. Chem."},{"key":"ref_120","first-page":"1058","article-title":"Telomere instability in a human tumor cell line expressing Nbs1 with mutations at sites phosphorylated by ATM","volume":"1","author":"Bai","year":"2003","journal-title":"Mol. Cancer Res."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1038\/sj.cr.7310007","article-title":"The role of Nbs1 in DNA double strand break repair, telomere stability, and cell cycle checkpoint control","volume":"16","author":"Zhang","year":"2006","journal-title":"Cell Res."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"962","DOI":"10.1016\/S0960-9822(01)00267-6","article-title":"Rescue of a telomere length defect of Nijmegen breakage syndrome cells requires Nbs and telomerase catalytic subunit","volume":"11","author":"Ranganathan","year":"2001","journal-title":"Curr. Biol."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"1003","DOI":"10.1084\/jem.20070319","article-title":"Distinct domains in Nbs1 regulate irradiation-induced checkpoints and apoptosis","volume":"204","author":"Difilippantonio","year":"2007","journal-title":"J. Exp. Med."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1002\/ajmg.1320400109","article-title":"Chromosome instability and X-ray hypersensitivity in a microcephalic and growth-retarded child","volume":"40","author":"Barbi","year":"1991","journal-title":"Am. J. Med. Genet"},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/j.biochi.2015.03.017","article-title":"Human RAD50 makes a functional DNA-binding complex","volume":"113","author":"Kinoshita","year":"2015","journal-title":"Biochim."},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"1415","DOI":"10.1016\/j.cell.2007.05.052","article-title":"Systematic discovery of in vivo phosphorylation networks","volume":"129","author":"Linding","year":"2007","journal-title":"Cell"},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"31542","DOI":"10.1074\/jbc.M111.258152","article-title":"ATM protein-dependent phosphorylation of RAD50 protein regulates DNA repair and cell cycle control","volume":"286","author":"Gatei","year":"2011","journal-title":"J. Biol. Chem."},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"808","DOI":"10.1038\/nsmb.1639","article-title":"Multiple functions of MRN in end-joining pathways during isotype class switching","volume":"16","author":"Dinkelmann","year":"2009","journal-title":"Nat. Struct. Mol. Biol."},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1016\/j.molcel.2007.10.016","article-title":"Ctp1\/CtIP and the mrn complex collaborate in the initial steps of homologous recombination","volume":"28","author":"Takeda","year":"2007","journal-title":"Mol. Cell"},{"key":"ref_130","first-page":"22939","article-title":"The mre11-rad50-nbs1 complex acts both upstream and downstream of ataxia telangiectasia mutated and RAD3-related protein (ATR) to regulate the S-phase checkpoint following UV treatment","volume":"282","author":"Olson","year":"2007","journal-title":"Nat. Struct. Mol. Biol."},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"9346","DOI":"10.1074\/jbc.M513265200","article-title":"Rapid activation of ATR by ionizing radiation requires ATM and MRE11","volume":"281","author":"Myers","year":"2006","journal-title":"J. Biol. Chem."},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1038\/sj.emboj.7600504","article-title":"Nbs1 is required for ATR-dependent phosphorylation events","volume":"24","author":"Stiff","year":"2005","journal-title":"EMBO J."},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1016\/j.molcel.2013.03.006","article-title":"A role for the mrn complex in ATR activation via TOPBP1 recruitment","volume":"50","author":"Duursma","year":"2013","journal-title":"Mol. Cell"},{"key":"ref_134","doi-asserted-by":"crossref","first-page":"4232","DOI":"10.1093\/hmg\/ddu141","article-title":"RAD50 phosphorylation promotes ATR downstream signaling and DNA restart following replication stress","volume":"23","author":"Gatei","year":"2014","journal-title":"Hum. Mol. Genet."},{"key":"ref_135","doi-asserted-by":"crossref","first-page":"4221","DOI":"10.1242\/jcs.004580","article-title":"Nbs1 mediates ATR-dependent RPA hyperphosphorylation following replication-fork stall and collapse","volume":"120","author":"Manthey","year":"2007","journal-title":"J. Cell Sci."},{"key":"ref_136","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1038\/nature05740","article-title":"The carboxy terminus of nbs1 is required for induction of apoptosis by the Mre11 complex","volume":"447","author":"Stracker","year":"2007","journal-title":"Nature"},{"key":"ref_137","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1038\/nature13751","article-title":"DNA repair: Making the cut","volume":"514","author":"Symington","year":"2014","journal-title":"Nature"},{"key":"ref_138","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1038\/nsmb.2038","article-title":"ABC ATPase signature helices in RAD50 link nucleotide state to MRE11 interface for DNA repair","volume":"18","author":"Williams","year":"2011","journal-title":"Nat. Struct. Mol. Biol."},{"key":"ref_139","doi-asserted-by":"crossref","first-page":"1091","DOI":"10.1101\/gad.2037811","article-title":"Crystal structure of the MRE11-RAD50-ATPgammas complex: Understanding the interplay between MRE11 and RAD50","volume":"25","author":"Lim","year":"2011","journal-title":"Genes Dev."},{"key":"ref_140","doi-asserted-by":"crossref","first-page":"3480","DOI":"10.1021\/pr300016e","article-title":"Phosphositeanalyzer: A bioinformatic platform for deciphering phospho proteomes using kinase predictions retrieved from networkin","volume":"11","author":"Bennetzen","year":"2012","journal-title":"J. Proteome Res."},{"key":"ref_141","doi-asserted-by":"crossref","first-page":"19513","DOI":"10.1074\/jbc.274.28.19513","article-title":"The nijmegen breakage syndrome protein is essential for MRE11 phosphorylation upon DNA damage","volume":"274","author":"Dong","year":"1999","journal-title":"J. Biol. Chem."},{"key":"ref_142","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1016\/S0300-483X(02)00220-2","article-title":"Neocarzinostatin induces mre11 phosphorylation and focus formation through an ATM- and Nbs1-dependent mechanism","volume":"177","author":"Yuan","year":"2002","journal-title":"Toxicol."},{"key":"ref_143","doi-asserted-by":"crossref","first-page":"1311","DOI":"10.1016\/j.dnarep.2009.07.006","article-title":"PIKK-dependent phosphorylation of MRE11 induces mrn complex inactivation by disassembly from chromatin","volume":"8","author":"Ying","year":"2009","journal-title":"DNA Repair"},{"key":"ref_144","doi-asserted-by":"crossref","first-page":"8352","DOI":"10.1093\/nar\/gkv754","article-title":"ATM-dependent phosphorylation of MRE11 controls extent of resection during homology directed repair by signalling through exonuclease 1","volume":"43","author":"Kijas","year":"2015","journal-title":"Nucleic Acids Res."},{"key":"ref_145","doi-asserted-by":"crossref","first-page":"350","DOI":"10.1101\/gad.2003811","article-title":"BLM-DNA2-RPA-MRN and EXO1-BLM-RPA-MRN constitute two DNA end resection machineries for human DNA break repair","volume":"25","author":"Nimonkar","year":"2011","journal-title":"Genes Dev."},{"key":"ref_146","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1038\/nature10515","article-title":"Bidirectional resection of DNA double-strand breaks by MRE11 and EXO1","volume":"479","author":"Garcia","year":"2011","journal-title":"Nature"},{"key":"ref_147","doi-asserted-by":"crossref","first-page":"2400","DOI":"10.1038\/emboj.2008.171","article-title":"Checkpoint-dependent phosphorylation of EXO1 modulates the DNA damage response","volume":"27","author":"Morin","year":"2008","journal-title":"EMBO J."},{"key":"ref_148","doi-asserted-by":"crossref","first-page":"1821","DOI":"10.1093\/nar\/gkp1164","article-title":"Phosphorylation of EXO1 modulates homologous recombination repair of DNA double-strand breaks","volume":"38","author":"Bolderson","year":"2010","journal-title":"Nucleic Acids Res."}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/5\/4\/2877\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T20:50:44Z","timestamp":1760215844000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/5\/4\/2877"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,10,23]]},"references-count":148,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2015,12]]}},"alternative-id":["biom5042877"],"URL":"https:\/\/doi.org\/10.3390\/biom5042877","relation":{},"ISSN":["2218-273X"],"issn-type":[{"value":"2218-273X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2015,10,23]]}}}