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DNA damage-induced allosteric activation of protein phosphatase PP1:NIPP1 through Src kinase-induced circularization of NIPP1.
- Source :
-
The FEBS journal [FEBS J] 2024 Jun; Vol. 291 (12), pp. 2615-2635. Date of Electronic Publication: 2024 Feb 01. - Publication Year :
- 2024
-
Abstract
- Protein phosphatase-1 (PP1) complexed to nuclear inhibitor of PP1 (NIPP1) limits DNA repair through dephosphorylation of NIPP1-recruited substrates. However, the PP1:NIPP1 holoenzyme is completely inactive under basal conditions, hinting at a DNA damage-regulated activation mechanism. Here, we report that DNA damage caused the activation of PP1:NIPP1 after a time delay of several hours through phosphorylation of NIPP1 at the C-terminal tyrosine 335 (Y335) by a Src-family kinase. PP1:NIPP1 activation partially resulted from the dissociation of the C terminus of NIPP1 from the active site of PP1. In addition, the released Y335-phosphorylated C terminus interacted with the N terminus of NIPP1 to enhance substrate recruitment by the flanking forkhead-associated (FHA) domain. Constitutive activation of PP1:NIPP1 by knock-in of a phospho-mimicking (Y335E) NIPP1 mutant led to the hypo-phosphorylation of FHA ligands and an accumulation of DNA double-strand breaks. Our data indicate that PP1:NIPP1 activation through circularization of NIPP1 is a late response to DNA damage that contributes to the timely recovery from damage repair.<br /> (© 2024 The Authors. The FEBS Journal published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)
- Subjects :
- Phosphorylation
Humans
DNA Repair
Allosteric Regulation
DNA Breaks, Double-Stranded
HEK293 Cells
Protein Binding
Intracellular Signaling Peptides and Proteins
Protein Phosphatase 1 metabolism
Protein Phosphatase 1 genetics
Protein Phosphatase 1 chemistry
DNA Damage
src-Family Kinases metabolism
src-Family Kinases genetics
src-Family Kinases chemistry
Subjects
Details
- Language :
- English
- ISSN :
- 1742-4658
- Volume :
- 291
- Issue :
- 12
- Database :
- MEDLINE
- Journal :
- The FEBS journal
- Publication Type :
- Academic Journal
- Accession number :
- 38303113
- Full Text :
- https://doi.org/10.1111/febs.17064