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EMBO J. 2006 Dec 13;25(24):5775-82. Epub 2006 Nov 23.

ATR-dependent phosphorylation and activation of ATM in response to UV treatment or replication fork stalling.

Author information

1
Genome Damage and Stability Centre, University of Sussex, Falmer, Brighton, East Sussex, UK.

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.

PMID:
17124492
PMCID:
PMC1698893
DOI:
10.1038/sj.emboj.7601446
[Indexed for MEDLINE]
Free PMC Article

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