The Wip1 phosphatase (PPM1D) antagonizes activation of the Chk2 tumour suppressor kinase.
We previously demonstrated that type 2C protein phosphatases (PP2C) Ptc2 and Ptc3 are required for DNA checkpoint inactivation after DNA double-strand break repair or adaptation in Saccharomyces cerevisiae. Here, we show the conservation of this pathway in mammalian cells. In response to DNA damage, ataxia telangiectasia mutated (ATM) phosphorylates the Chk2 tumour suppressor kinase at threonine 68 (Thr68), allowing Chk2 kinase dimerization and activation by autophosphorylations in the T-loop. The oncogenic protein Wip1, a PP2C phosphatase, binds Chk2 and dephosphorylates phospho-Thr68. Consequently, Wip1 opposes Chk2 activation by ATM after ionizing irradiation of cells. In HCT15 colorectal cancer cells corrected for functional Chk2 activity, Wip1 overexpression suppressed the contribution of Chk2 to the G2/M DNA damage checkpoint. These results indicate that Wip1 is one of the phosphatases regulating the activity of Chk2 in response to DNA damage.
Oliva-Trastoy
M
M
Service de Biochimie et de Génétique Moléculaire, CEA/Saclay, Gif-sur-Yvette, France.
Berthonaud
V
V
Chevalier
A
A
Ducrot
C
C
Marsolier-Kergoat
M-C
MC
Mann
C
C
Leteurtre
F
F
D064007:Ataxia Telangiectasia Mutated Proteins; D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000494:pharmacology / Q000528:radiation effects; D064447:Checkpoint Kinase 2; D015179:Colorectal Neoplasms / Q000378:metabolism; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000494:pharmacology / Q000528:radiation effects; D004789:Enzyme Activation; D006801:Humans; D010749:Phosphoprotein Phosphatases / Q000494:pharmacology*; D010766:Phosphorylation; D000071636:Protein Phosphatase 2C; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis* / Q000494:pharmacology / Q000528:radiation effects; D029701:Saccharomyces cerevisiae Proteins; D013912:Threonine / Q000378:metabolism; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis* / Q000494:pharmacology / Q000528:radiation effects
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D029701:Saccharomyces cerevisiae Proteins; D025521:Tumor Suppressor Proteins; D013912:Threonine; D064447:Checkpoint Kinase 2; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C578634:CHEK2 protein, human; D017346:Protein Serine-Threonine Kinases; C000607458:PPM1D protein, human; C000607464:PTC3 protein, S cerevisiae; D010749:Phosphoprotein Phosphatases; D000071636:Protein Phosphatase 2C