title: ATM-Dependent Phosphorylation of All Three Members of the MRN Complex: From Sensor to Adaptor.
abstract: 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.
authors.affiliation: UQ Centre for Clinical Research, The University of Queensland, Brisbane, QLD 4029, Australia. m.lavin@uq.edu.au.
authors.forename: Martin F
authors.initials: MF
authors.lastname: Lavin
authors.affiliation: UQ Centre for Clinical Research, The University of Queensland, Brisbane, QLD 4029, Australia. s.kozlov@uq.edu.au.
authors.forename: Sergei
authors.initials: S
authors.lastname: Kozlov
authors.affiliation: UQ Centre for Clinical Research, The University of Queensland, Brisbane, QLD 4029, Australia. m.gatei@uq.edu.au.
authors.forename: Magtouf
authors.initials: M
authors.lastname: Gatei
authors.affiliation: UQ Centre for Clinical Research, The University of Queensland, Brisbane, QLD 4029, Australia. a.kijas@uq.edu.au.
authors.forename: Amanda W
authors.initials: AW
authors.lastname: Kijas
mesh_terms: D017766:Acid Anhydride Hydrolases; D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000378:metabolism*; D053903:DNA Breaks, Double-Stranded; D045643:DNA Repair Enzymes / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D006801:Humans; D000076228:MRE11 Homologue Protein; D009687:Nuclear Proteins / Q000378:metabolism*; D018384:Oxidative Stress; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D015398:Signal Transduction
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C121766:MRE11 protein, human; C112156:NBN protein, human; D009687:Nuclear Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D000076228:MRE11 Homologue Protein; D017766:Acid Anhydride Hydrolases; C112158:RAD50 protein, human; D045643:DNA Repair Enzymes
keywords: ATM activation; DNA double strand breaks; Mre11/Rad50/Nbs1 complex; adaptor role; oxidative stress; phosphorylation