Oocyte DNA damage quality control requires consecutive interplay of CHK2 and CK1 to activate p63.
Nat Struct Mol Biol
; 25(3): 261-269, 2018 03.
Article
en En
| MEDLINE
| ID: mdl-29483652
ABSTRACT
The survival rate of cancer patients is steadily increasing, owing to more efficient therapies. Understanding the molecular mechanisms of chemotherapy-induced premature ovarian insufficiency (POI) could identify targets for prevention of POI. Loss of the primordial follicle reserve is the most important cause of POI, with the p53 family member p63 being responsible for DNA-damage-induced apoptosis of resting oocytes. Here, we provide the first detailed mechanistic insight into the activation of p63, a process that requires phosphorylation by both the priming kinase CHK2 and the executioner kinase CK1 in mouse primordial follicles. We further describe the structural changes induced by phosphorylation that enable p63 to adopt its active tetrameric conformation and demonstrate that previously discussed phosphorylation by c-Abl is not involved in this process. Inhibition of CK1 rescues primary oocytes from doxorubicin and cisplatin-induced apoptosis, thus uncovering a new target for the development of fertoprotective therapies.
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Oocitos
/
Factores de Transcripción
/
Daño del ADN
/
Proteínas Supresoras de Tumor
/
Quinasa de la Caseína I
/
Quinasa de Punto de Control 2
Tipo de estudio:
Prognostic_studies
Límite:
Animals
/
Humans
Idioma:
En
Año:
2018
Tipo del documento:
Article