Journal
EMBO JOURNAL
Volume 25, Issue 24, Pages 5775-5782Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/sj.emboj.7601446
Keywords
ataxia telangiectasia-mutated protein; DNA damage responses; phosphorylation; PIKKs
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Funding
- Medical Research Council [G0300662B, G0500897] Funding Source: researchfish
- MRC [G0500897] Funding Source: UKRI
- Medical Research Council [G0500897] Funding Source: Medline
- NCI NIH HHS [CA 57569, R01 CA057569] Funding Source: Medline
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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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