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

Stiff, Thomas, Walker, Sarah, Cerosaletti, Karen, Goodarzi, Aaron, Petermann, Mylene Pamela, Concannon, Pat, O'Driscoll, Mark and Jeggo, Penny (2006) ATR-dependent phosphorylation and activation of ATM in response to UV treatment or replication fork stalling. EMBO Journal, 25 (24). pp. 5775-5782. ISSN 0261-4189

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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.

Item Type: Article
Keywords: Ataxia telangiectasia-mutated protein, DNA damage responses, phosphorylation, PIKKs
Schools and Departments: School of Life Sciences > Biochemistry
Subjects: Q Science > QD Chemistry
Q Science > QH Natural history > QH0301 Biology
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Depositing User: Gee Wheatley
Date Deposited: 15 Feb 2008
Last Modified: 17 Jul 2012 11:22
URI: http://sro.sussex.ac.uk/id/eprint/726
Google Scholar:146 Citations
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