Harmonising the response to DSBs: a new string in the ATM bow.
Ataxia telangiestasia mutated protein (ATM) is the major kinase that initiates the DNA damage signal transduction response following exposure to ionising radiation (IR) in mammalian cells. DNA non-homologous end-joining (NHEJ) is the most significant double strand break (DSB) repair pathway in mammalian cells. ATM-defective cell lines display cell cycle checkpoint defects and show pronounced radiosensitivity. ATM signalling was previously thought to be dispensable for NHEJ. This review discusses recent findings that ATM activates an end-processing mechanism dependent upon Artemis, a nuclease that also functions to cleave the hairpin intermediate generated during V(D)J recombination. ATM/Artemis-dependent end-processing is required for the repair of a sub-fraction (approximately 10%) of DSBs induced by IR and makes a significant contribution to survival following exposure to ionising radiation. This result represents a new role for ATM and demonstrates a novel cross communication between the DNA repair and signal transduction machinery.
Löbrich
Markus
M
Fachrichtung Biophysik, Universität des Saarlandes, D-66421 Homburg/Saar, Germany. markus.loebrich@uniklinik-saarland.de
Jeggo
Penny A
PA
D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D004249:DNA Damage; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004720:Endonucleases; D015321:Gene Rearrangement; D006801:Humans; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D011836:Radiation Tolerance / Q000235:genetics*; D011995:Recombination, Genetic; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins / Q000235:genetics / 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