Artemis links ATM to double strand break rejoining.
Ataxia telangiectasia mutated protein (ATM) is a damage response kinase that initiates a signal transduction response to the presence of DNA double strand breaks (DSBs) regulating cell cycle checkpoint arrest and apoptosis. Indirect evidence has argued that A-T cells also harbour a repair defect since unrepaired DSBs can be observed in non-replicating A-T cells after ionising radiation (IR). The basis underlying such a repair defect has remained unexplained, however. Artemis, a nuclease, whose activity is modified by phosphorylation in vitro, was recently identified as a novel ATM substrate. Artemis and ATM function in a common pathway required for the processing of a subset of double stranded DNA ends induced by IR prior to rejoining by non-homologous end-joining (NHEJ). This subset of DSBs are those normally rejoined with slow kinetics. Additional components of the ATM signal transduction pathway, Nbs1, Mre11, H2AX and 53BP1, are also required for this component of DSB repair. This process substantially contributes to survival post irradiation. Our findings add a new dimension to the ATM signal transduction response demonstrating ATM-dependent regulation of an end-processing mechanism that functions during the cell cycle delay effected by ATM.
Jeggo
Penny A
PA
Genome Damage and Stability Centre, University of Sussex, East Sussex, UK. p.a.jeggo@sussex.ac.uk
Löbrich
Markus
M
D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000378:metabolism; D004249:DNA Damage; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism; D004720:Endonucleases; D005786:Gene Expression Regulation; D006801:Humans; D007700:Kinetics; D008954:Models, Biological; D009687:Nuclear Proteins / Q000502:physiology*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins / Q000378:metabolism
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases; C426344:DCLRE1C protein, human; D004720:Endonucleases