DNA damage-induced allosteric activation of protein phosphatase PP1:NIPP1 through Src kinase-induced circularization of NIPP1.
FEBS J
; 291(12): 2615-2635, 2024 Jun.
Article
en En
| MEDLINE
| ID: mdl-38303113
ABSTRACT
Protein phosphatase-1 (PP1) complexed to nuclear inhibitor of PP1 (NIPP1) limits DNA repair through dephosphorylation of NIPP1-recruited substrates. However, the PP1NIPP1 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 PP1NIPP1 after a time delay of several hours through phosphorylation of NIPP1 at the C-terminal tyrosine 335 (Y335) by a Src-family kinase. PP1NIPP1 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 PP1NIPP1 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 PP1NIPP1 activation through circularization of NIPP1 is a late response to DNA damage that contributes to the timely recovery from damage repair.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Daño del ADN
/
Familia-src Quinasas
/
Proteína Fosfatasa 1
Límite:
Humans
Idioma:
En
Revista:
FEBS J
Asunto de la revista:
BIOQUIMICA
Año:
2024
Tipo del documento:
Article
País de afiliación:
Bélgica
Pais de publicación:
Reino Unido