| Title: |
DNA damage-induced allosteric activation of protein phosphatase PP1:NIPP1 through Src kinase-induced circularization of NIPP1 |
| Authors: |
Wu, Dan; Van der Hoeven, Gerd; Claes, Zander; Van Eynde, Aleyde; Bollen, Mathieu |
| Source: |
ISSN:1742-464X ; ISSN:1742-4658 ; Febs Journal, vol. 291 (12), (2615-2635. |
| Publisher Information: |
Published by Springer-Verlag on behalf of the Federation of European Biochemical Societies |
| Publication Year: |
2024 |
| Subject Terms: |
Science & Technology; Life Sciences & Biomedicine; Biochemistry & Molecular Biology; DNA damage; NIPP1; PP1; protein dephosphorylation; Src-family kinases; NUCLEAR INHIBITOR; PHOSPHORYLATION; SUBUNIT; BINDING; EZH2; OCCUPANCY; CDC5L; Src‐family kinases; Humans; Protein Phosphatase 1; DNA Repair; Allosteric Regulation; DNA Breaks; Double-Stranded; HEK293 Cells; Protein Binding; Intracellular Signaling Peptides and Proteins; 0304 Medicinal and Biomolecular Chemistry; 0601 Biochemistry and Cell Biology; 1101 Medical Biochemistry and Metabolomics; 3101 Biochemistry and cell biology; 3205 Medical biochemistry and metabolomics |
| Description: |
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. ; sponsorship: This work was financially supported by the Foundation Against Cancer (2020-065) and the Special Research Fund of KU Leuven (BOF C14/20/101). We thank Monique Beullens and Janina Goernemann for the generation of the phospho-epitope-specific NIPP1-Y335 and monoclonal NIPP1 antibodies, respectively. (Foundation Against Cancer, Special Research Fund of KU Leuven|2020-065, BOF C14/20/101) ; status: Published |
| Document Type: |
article in journal/newspaper |
| File Description: |
application/pdf |
| Language: |
English |
| Relation: |
https://lirias.kuleuven.be/handle/20.500.12942/735949; https://doi.org/10.1111/febs.17064; https://pubmed.ncbi.nlm.nih.gov/38303113 |
| DOI: |
10.1111/febs.17064 |
| Availability: |
https://lirias.kuleuven.be/handle/20.500.12942/735949; https://hdl.handle.net/20.500.12942/735949; https://lirias.kuleuven.be/retrieve/617669de-c424-450c-acb0-e29776e32f40; https://doi.org/10.1111/febs.17064; https://pubmed.ncbi.nlm.nih.gov/38303113 |
| Rights: |
info:eu-repo/semantics/openAccess ; public ; https://creativecommons.org/licenses/by-nc-nd/4.0/ |
| Accession Number: |
edsbas.7D7E26E9 |
| Database: |
BASE |