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1.
Proc Natl Acad Sci U S A ; 121(19): e2401386121, 2024 May 07.
Artículo en Inglés | MEDLINE | ID: mdl-38696471

RESUMEN

In the meiotic prophase, programmed DNA double-strand breaks are repaired by meiotic recombination. Recombination-defective meiocytes are eliminated to preserve genome integrity in gametes. BRCA1 is a critical protein in somatic homologous recombination, but studies have suggested that BRCA1 is dispensable for meiotic recombination. Here we show that BRCA1 is essential for meiotic recombination. Interestingly, BRCA1 also has a function in eliminating recombination-defective oocytes. Brca1 knockout (KO) rescues the survival of Dmc1 KO oocytes far more efficiently than removing CHK2, a vital component of the DNA damage checkpoint in oocytes. Mechanistically, BRCA1 activates chromosome asynapsis checkpoint by promoting ATR activity at unsynapsed chromosome axes in Dmc1 KO oocytes. Moreover, Brca1 KO also rescues the survival of asynaptic Spo11 KO oocytes. Collectively, our study not only unveils an unappreciated role of chromosome asynapsis in eliminating recombination-defective oocytes but also reveals the dual functions of BRCA1 in safeguarding oocyte genome integrity.


Asunto(s)
Proteína BRCA1 , Proteínas de Ciclo Celular , Ratones Noqueados , Oocitos , Oocitos/metabolismo , Animales , Proteína BRCA1/genética , Proteína BRCA1/metabolismo , Femenino , Ratones , Proteínas de Ciclo Celular/metabolismo , Proteínas de Ciclo Celular/genética , Meiosis/genética , Proteínas de la Ataxia Telangiectasia Mutada/genética , Proteínas de la Ataxia Telangiectasia Mutada/metabolismo , Proteínas de la Ataxia Telangiectasia Mutada/deficiencia , Roturas del ADN de Doble Cadena , Emparejamiento Cromosómico/genética , Endodesoxirribonucleasas/metabolismo , Endodesoxirribonucleasas/genética , Quinasa de Punto de Control 2/genética , Quinasa de Punto de Control 2/metabolismo , Proteínas de Unión a Fosfato/metabolismo , Proteínas de Unión a Fosfato/genética , Recombinación Genética , Recombinación Homóloga , Inestabilidad Genómica
2.
Cell Death Differ ; 27(9): 2552-2567, 2020 09.
Artículo en Inglés | MEDLINE | ID: mdl-32139898

RESUMEN

BRCA1 is critical for DNA double-strand break (DSB) repair by homologous recombination (HR). BRCA1 deficient mice are embryonic lethal. Previous studies have shown that 53BP1 knockout (KO) rescues embryonic lethality of BRCA1 hypomorphic mutant mice by restoring HR. Here, we show that 53BP1 KO can partially rescue embryonic lethality of BRCA1 total KO mice, but HR is not restored in BRCA1-53BP1 double knockout (DKO) mice. As a result, BRCA1-53BP1 DKO cells are extremely sensitive to PARP inhibitors (PARPi). In addition to HR deficiency, BRCA1-53BP1 DKO cells have elevated microhomology-mediated end joining (MMEJ) activity and G2/M cell cycle checkpoint defects, causing severe genomic instability in these cells. Interestingly, BRCA1-53BP1 DKO mice rapidly develop thymic lymphoma that is 100% penetrant, which is not observed in any BRCA1 mutant mice rescued by 53BP1 KO. Taken together, our study reveals that 53BP1 KO can partially rescue embryonic lethality caused by complete BRCA1 loss without rescuing HR-related defects. This finding suggests that loss of 53BP1 can support the development of cancers with silenced BRCA1 expression without causing PARPi resistance.


Asunto(s)
Proteína BRCA1/deficiencia , Pérdida del Embrión/genética , Inestabilidad Genómica , Proteína 1 de Unión al Supresor Tumoral P53/deficiencia , Animales , Proteína BRCA1/química , Proteína BRCA1/metabolismo , Puntos de Control del Ciclo Celular , Línea Celular Tumoral , Aberraciones Cromosómicas , Roturas del ADN de Doble Cadena , Reparación del ADN por Unión de Extremidades , Reparación del ADN , Supervivencia sin Enfermedad , Pérdida del Embrión/patología , Silenciador del Gen , Recombinación Homóloga , Humanos , Linfoma/patología , Metafase , Ratones Endogámicos C57BL , Ratones Noqueados , Modelos Biológicos , Dominios Proteicos , Timo/patología , Proteína 1 de Unión al Supresor Tumoral P53/metabolismo
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