ATM and Chk2 kinase target the p53 cofactor Strap.
The p53 cofactor Strap (stress responsive activator of p300) is directly targeted by the DNA damage signalling pathway where phosphorylation by ATM (ataxia telangiectasia mutated) kinase facilitates nuclear accumulation. Here, we show that Strap regulation reflects the coordinated interplay between different DNA damage-activated protein kinases, ATM and Chk2 (Checkpoint kinase 2), where phosphorylation by each kinase provides a distinct functional consequence on the activity of Strap. ATM phosphorylation prompts nuclear accumulation, which we show occurs by impeding nuclear export, whereas Chk2 phosphorylation augments protein stability once Strap has attained a nuclear location. These results highlight the various functional roles undertaken by the DNA damage signalling kinases in Strap control and, more generally, shed light on the pathways that contribute to the regulation of the p53 response.
Adams
Cassandra J
CJ
Laboratory of Cancer Biology, Medical Sciences Division, Department of Clinical Pharmacology, University of Oxford, Oxford OX3 7DQ, UK.
Graham
Anne L
AL
Jansson
Martin
M
Coutts
Amanda S
AS
Edelmann
Mariola
M
Smith
Linda
L
Kessler
Benedikt
B
La Thangue
Nicholas B
NB
D021581:Active Transport, Cell Nucleus; D000595:Amino Acid Sequence; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D064447:Checkpoint Kinase 2; D004268:DNA-Binding Proteins / Q000378:metabolism*; D006801:Humans; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000737:chemistry / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D055550:Protein Stability; D016601:RNA-Binding Proteins; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D009363:Neoplasm Proteins; D016601:RNA-Binding Proteins; C403447:STRAP protein, human; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D064447:Checkpoint Kinase 2; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C578634:CHEK2 protein, human; D017346:Protein Serine-Threonine Kinases