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

journal contribution
posted on 2023-06-07, 13:42 authored by Thomas StiffThomas Stiff, Sarah A Walker, Karen Cerosaletti, Aaron A Goodarzi, Eve Petermann, Pat Concannon, Mark O'DriscollMark O'Driscoll, Penny Jeggo
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. ATRdependent 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.

History

Publication status

  • Published

Journal

EMBO Journal

ISSN

0261-4189

Publisher

EMBO Press

Issue

24

Volume

25

Page range

5775-5782

Department affiliated with

  • Biochemistry Publications

Full text available

  • No

Peer reviewed?

  • Yes

Legacy Posted Date

2008-02-15

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