title: ATR-dependent phosphorylation and activation of ATM in response to UV treatment or replication fork stalling.
abstract: The phosphatidyl inositol 3-kinase-like kinases (PIKKs), ataxia-telangiectasia mutated (ATM) and ATM- and Rad3-related (ATR) regulate parallel damage response signalling pathways. ATM is reported to be activated by DNA double-strand breaks (DSBs), whereas ATR is recruited to single-stranded regions of DNA. Although the two pathways were considered to function independently, recent studies have demonstrated that ATM functions upstream of ATR following exposure to ionising radiation (IR) in S/G2. Here, we show that ATM phosphorylation at Ser1981, a characterised autophosphorylation site, is ATR-dependent and ATM-independent following replication fork stalling or UV treatment. In contrast to IR-induced ATM-S1981 phosphorylation, UV-induced ATM-S1981 phosphorylation does not require the Nbs1 C-terminus or Mre11. ATR-dependent phosphorylation of ATM activates ATM phosphorylation of Chk2, which has an overlapping function with Chk1 in regulating G2/M checkpoint arrest. Our findings provide insight into the interplay between the PIKK damage response pathways.
authors.affiliation: Genome Damage and Stability Centre, University of Sussex, Falmer, Brighton, East Sussex, UK.
authors.forename: Thomas
authors.initials: T
authors.lastname: Stiff
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Walker
authors.forename: Karen
authors.initials: K
authors.lastname: Cerosaletti
authors.forename: Aaron A
authors.initials: AA
authors.lastname: Goodarzi
authors.forename: Eva
authors.initials: E
authors.lastname: Petermann
authors.forename: Pat
authors.initials: P
authors.lastname: Concannon
authors.forename: Mark
authors.initials: M
authors.lastname: O'Driscoll
authors.forename: Penny A
authors.initials: PA
authors.lastname: Jeggo
mesh_terms: D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000378:metabolism*; D000071877:Checkpoint Kinase 1; D064447:Checkpoint Kinase 2; D004261:DNA Replication / Q000187:drug effects / Q000528:radiation effects; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects / Q000528:radiation effects; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000473:pathology / Q000528:radiation effects; D016195:G2 Phase / Q000187:drug effects / Q000528:radiation effects; D006657:Histones / Q000172:deficiency; D006801:Humans; D006918:Hydroxyurea / Q000494:pharmacology; D051379:Mice; D008938:Mitosis / Q000187:drug effects / Q000528:radiation effects; D008954:Models, Biological; D009687:Nuclear Proteins / Q000378:metabolism; D010750:Phosphoproteins / Q000172:deficiency; D010766:Phosphorylation / Q000187:drug effects / Q000528:radiation effects; D010768:Phosphoserine / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D014466:Ultraviolet Rays
chemical_list: D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins; D000071877:Checkpoint Kinase 1; D064447:Checkpoint Kinase 2; D004268:DNA-Binding Proteins; D006657:Histones; D006918:Hydroxyurea; D009687:Nuclear Proteins; D010750:Phosphoproteins; D010768:Phosphoserine; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D025521:Tumor Suppressor Proteins; C112156:NBN protein, human; C576324:ATM protein, human; C576597:ATR protein, human; C576325:Atm protein, mouse; C000605867:CHEK1 protein, human; C578634:CHEK2 protein, human; C000605869:Chek1 protein, mouse; C578633:Chek2 protein, mouse; C475961:gamma-H2AX protein, mouse