Conserved modes of recruitment of ATM, ATR and DNA-PKcs to sites of DNA damage.
Ataxia-telangiectasia mutated (ATM), ataxia-telangiectasia and Rad3-related (ATR) and DNA-dependent protein kinase catalytic subunit (DNA-PKcs) are members of the phosphoinositide-3-kinase-related protein kinase (PIKK) family, and are rapidly activated in response to DNA damage. ATM and DNA-PKcs respond mainly to DNA double-strand breaks, whereas ATR is activated by single-stranded DNA and stalled DNA replication forks. In all cases, activation involves their recruitment to the sites of damage. Here we identify related, conserved carboxy-terminal motifs in human Nbs1, ATRIP and Ku80 proteins that are required for their interaction with ATM, ATR and DNA-PKcs, respectively. These motifs are essential not only for efficient recruitment of ATM, ATR and DNA-PKcs to sites of damage, but are also critical for ATM-, ATR- and DNA-PKcs-mediated signalling events that trigger cell cycle checkpoints and DNA repair. Our findings reveal that recruitment of these PIKKs to DNA lesions occurs by common mechanisms through an evolutionarily conserved motif, and provide direct evidence that PIKK recruitment is required for PIKK-dependent DNA-damage signalling.
Falck
Jacob
J
The Wellcome Trust and Cancer Research UK Gurdon Institute, and Department of Zoology, Cambridge University, Tennis Court Road, Cambridge CB2 1QN, UK.
Coates
Julia
J
Jackson
Stephen P
SP
D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D034961:Antigens, Nuclear / Q000737:chemistry / Q000378:metabolism; D064007:Ataxia Telangiectasia Mutated Proteins; D001665:Binding Sites; D018797:Cell Cycle Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D017124:Conserved Sequence; D006224:Cricetinae; D004247:DNA / Q000235:genetics / Q000378:metabolism; D004249:DNA Damage; D051747:DNA-Activated Protein Kinase; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D000072200:Ku Autoantigen; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000737:chemistry; D010766:Phosphorylation; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D021381:Protein Transport; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
D034961:Antigens, Nuclear; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins; D004247:DNA; D051747:DNA-Activated Protein Kinase; D004268:DNA-Binding Proteins; D000072200:Ku Autoantigen; D009687:Nuclear Proteins; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D025521:Tumor Suppressor Proteins; C112156:NBN protein, human; C576324:ATM protein, human; C576597:ATR protein, human; C497263:PRKDC protein, human; C000606509:Xrcc6 protein, human