ATR-dependent Phosphorylation and Activation of ATM in Response to UV Treatment or Replication Fork Stalling

Overview

Journal EMBO J

Specialties Biotechnology
Molecular Biology

Date 2006 Nov 25

PMID 17124492

Citations 189

Authors

Thomas Stiff

Sarah A Walker

Karen Cerosaletti

Aaron A Goodarzi

Eva Petermann

Pat Concannon

Mark ODriscoll

Penny A Jeggo

Affiliations

Soon will be listed here.

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.

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