Article
- The EMBO Journal (2006) 25, 5775 - 5782
- doi:10.1038/sj.emboj.7601446
Published online: 23 November 2006
Subject Category:
ATR-dependent phosphorylation and activation of ATM in response to UV treatment or replication fork stalling
Thomas Stiff1, Sarah A Walker1, Karen Cerosaletti2, Aaron A Goodarzi1, Eva Petermann1, Pat Concannon2, Mark O'Driscoll1 and Penny A Jeggo1
- Genome Damage and Stability Centre, University of Sussex, Sussex, UK
- Molecular Genetics Program, Benaroya Research Institute, Seattle, WA, USA
Correspondence to:
Penny A Jeggo, Genome Damage and Stability Centre, University of Sussex, Falmer, Brighton, UK-East Sussex BN1 9RQ, UK. Tel.: +44 1273 678482; Fax: +44 1273 678121; E-mail: P.A.Jeggo@sussex.ac.uk
Received 6 April 2006; Accepted 23 October 2006
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.
Keywords:
- ataxia telangiectasia-mutated protein,
- DNA damage responses,
- phosphorylation,
- PIKKs
